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Objective: To expand the limited knowledge on cell-free DNA (cfDNA) analysis of maternal blood for trisomies 21, 18 and 13 in twin pregnancy by updating the data from The Fetal Medicine Foundation (FMF) on prospective first-trimester screening and those identified in a systematic review of the literature., Methods: The FMF data were derived from prospective screening for trisomies 21, 18 and 13 in twin pregnancies at 10 + 0 to 14 + 1 weeks' gestation using the Harmony® prenatal test. A search of MEDLINE, EMBASE, CENTRAL (The Cochrane Library), ClinicalTrials.gov and the International Clinical Trials Registry Platform (World Health Organization) was carried out to identify all peer-reviewed publications on clinical validation or implementation of maternal cfDNA testing for trisomies 21, 18 and 13 in twin pregnancy, irrespective of gestational age at testing, in which data on pregnancy outcome were provided for at least 85% of the study population. Meta-analysis was performed using the FMF data and data from the studies identified by the literature search. This review was registered in the PROSPERO international database for systematic reviews RESULTS: In the FMF study, cfDNA testing was carried out in 1442 twin pregnancies and a result was obtained, after first or second sampling, in 1367 (94.8%) cases. In 93.1% (1272/1367) of cases, there was prenatal or postnatal karyotyping or birth of phenotypically normal babies; 95 cases were excluded from further analysis either because the pregnancy ended in termination, miscarriage or stillbirth with no known karyotype (n = 56) or there was loss to follow-up (n = 39). In the 1272 pregnancies included in the study, there were 20 cases with trisomy 21, 10 with trisomy 18, two with trisomy 13 and 1240 without trisomy 21, 18 or 13. The cfDNA test classified correctly 19 (95.0%) of the 20 cases of trisomy 21, nine (90.0%) of the 10 cases of trisomy 18, one (50.0%) of the two cases of trisomy 13 and 1235 (99.6%) of the 1240 cases without any of the three trisomies. The literature search identified 12 relevant studies, excluding our papers because their data are included in the current study. In the combined populations of our study and the 12 studies identified by the literature search, there were 137 trisomy-21 and 7507 non-trisomy-21 twin pregnancies; the pooled weighted detection rate (DR) and false-positive rate (FPR) were 99.0% (95% CI, 92.0-99.9%) and 0.02% (95% CI, 0.001-0.43%), respectively. In the combined total of 50 cases of trisomy 18 and 6840 non-trisomy-18 pregnancies, the pooled weighted DR and FPR were 92.8% (95% CI, 77.6-98.0%) and 0.01% (95% CI, 0.00-0.44%), respectively. In the combined total of 11 cases of trisomy 13 and 6290 non-trisomy-13 pregnancies, the pooled weighted DR and FPR were 94.7% (95% CI, 9.14-99.97%) and 0.10% (95% CI, 0.03-0.39%), respectively., Conclusions: In twin pregnancy, the reported DR of trisomy 21 by cfDNA testing is high, but lower than that in singleton pregnancy, whereas the FPR appears to be equally low. The number of cases of trisomy 18 and more so trisomy 13 was too small for accurate assessment of the predictive performance of the cfDNA test. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To report on the routine clinical implementation of cell-free DNA (cfDNA) analysis of maternal blood for trisomies 21, 18 and 13 in twin pregnancy and to define the performance of the test by combining our results with those identified in a systematic review of the literature., Methods: The data for the prospective study were derived from screening for trisomies 21, 18 and 13 in twin pregnancies at 10 + 0 to 14 + 1 weeks' gestation. Two populations were included; first, self-referred women to the Fetal Medicine Centre in London or Brugmann University Hospital in Brussels and, second, women selected for the cfDNA test after routine first-trimester combined testing at one of two National Health Service hospitals in England. This dataset was used to determine the performance of screening for the three trisomies. Search of MEDLINE, EMBASE, CENTRAL (The Cochrane Library), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP) was carried out to identify all peer-reviewed publications on clinical validation or implementation of maternal cfDNA testing for trisomies 21, 18 and 13 in twin pregnancy. A meta-analysis was then performed using our data and those in the studies identified by the literature search., Results: In our dataset of 997 twin pregnancies with a cfDNA result and known outcome, the test classified correctly 16 (94.1%) of the 17 cases of trisomy 21, nine (90.0%) of the 10 cases of trisomy 18, one (50.0%) of the two cases of trisomy 13 and 962 (99.4%) of the 968 cases without any of the three trisomies. The literature search identified seven relevant studies, excluding our previous papers because their data are included in the current study. In the combined populations of our study and the seven studies identified by the literature search, there were 56 trisomy-21 and 3718 non-trisomy-21 twin pregnancies; the pooled weighted detection rate (DR) and false-positive rate (FPR) were 98.2% (95% CI, 83.2-99.8%) and 0.05% (95% CI, 0.01-0.26%), respectively. In the combined total of 18 cases of trisomy 18 and 3143 non-trisomy-18 pregnancies, the pooled weighted DR and FPR were 88.9% (95% CI, 64.8-97.2%) and 0.03% (95% CI, 0.00-0.33%), respectively. For trisomy 13, there were only three affected cases and two (66.7%) of these were detected by the cfDNA test at a FPR of 0.19% (5/2569)., Conclusions: The performance of cfDNA testing for trisomy 21 in twin pregnancy is similar to that reported in singleton pregnancy and is superior to that of the first-trimester combined test or second-trimester biochemical testing. The number of cases of trisomies 18 and 13 is too small for accurate assessment of the predictive performance of the cfDNA test. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To examine factors affecting the rate of failure to obtain a result from cell-free DNA (cfDNA) testing of maternal blood for fetal trisomies 21, 18 and 13 in singleton and twin pregnancies in the first trimester., Methods: This was a prospective study of 23 495 singleton and 928 twin pregnancies undergoing screening for fetal trisomy by targeted cfDNA testing at 10 + 0 to 14 + 1 weeks' gestation. Multivariate logistic regression analysis was used to determine significant predictors of failure to obtain a result after first sampling., Results: There was no result from cfDNA testing after first sampling in 3.4% (798/23 495) of singletons, 11.3% (91/806) of dichorionic twins and 4.9% (6/122) of monochorionic twins. Multivariate logistic regression analysis demonstrated that the risk of test failure, first, increased with increasing maternal age (odds ratio (OR), 1.02; 95% CI, 1.01-1.04) and weight (OR, 1.05; 95% CI, 1.04-1.05), decreasing gestational age (OR, 0.85; 95% CI, 0.79-0.91), serum pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) (OR, 0.56; 95% CI, 0.49-0.65) and free β-human chorionic gonadotropin (β-hCG) MoM (OR, 0.67; 95% CI, 0.60-0.74), second, was higher in women of black (OR, 1.72; 95% CI, 1.33-2.20) and South Asian (OR, 1.99; 95% CI, 1.56-2.52) than those of white racial origin, in dichorionic twin than in singleton pregnancy (OR, 1.75; 95% CI, 1.34-2.26) and in pregnancies conceived by in-vitro fertilization than in those conceived naturally (OR, 3.82; 95% CI, 3.19-4.55) and, third, was lower in parous than in nulliparous women (OR, 0.63; 95% CI, 0.55-0.74)., Conclusions: Maternal age, weight, racial origin and parity, gestational age, dichorionicity, method of conception and serum levels of free β-hCG and PAPP-A are independent predictors of cfDNA test failure. The risk of test failure is higher in dichorionic twin than in singleton pregnancies, mainly because a higher proportion of twins are conceived by in-vitro fertilization and more of the women are nulliparous. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: Cell-free DNA (cfDNA) analysis of maternal blood for detection of trisomies 21, 18 and 13 is superior to other methods of screening but is expensive. One strategy to maximize performance at reduced cost is to offer cfDNA testing contingent on the results of the first-trimester combined test that is used currently. The objectives of this study were to report the feasibility of implementing such screening, to examine the factors affecting patient decisions concerning their options for screening and decisions on the management of affected pregnancies and to report the prenatal diagnosis of fetal trisomies and outcome of affected pregnancies following the introduction of contingent screening., Methods: We examined routine clinical implementation of contingent screening in 11,692 singleton pregnancies in two National Health Service (NHS) hospitals in the UK. Women with a risk ≥ 1 in 100 (high-risk group) were offered options of invasive testing, cfDNA testing or no further testing, and those with a risk between 1 in 101 and 1 in 2500 (intermediate-risk group) were offered cfDNA testing or no further testing. The trisomic status of the pregnancies was determined by prenatal or postnatal karyotyping or by examination of the neonates., Results: In the study population of 11,692 pregnancies, there were 47 cases of trisomy 21 and 28 of trisomies 18 or 13. Screening with the combined test followed by invasive testing for all patients in the high-risk group potentially could have detected 87% of trisomy 21 and 93% of trisomies 18 or 13, at a false-positive rate of 3.4%; the respective values for cfDNA testing in the high- and intermediate-risk groups were 98%, 82% and 0.25%. However, in the high-risk group, 38% of women chose invasive testing and 60% chose cfDNA testing; in the intermediate-risk group 92% opted for cfDNA testing. A prenatal diagnosis was made in 43 (91.5%) pregnancies with trisomy 21 and all pregnancies with trisomies 18 or 13. In many affected pregnancies the parents chose to avoid testing or termination and 32% of pregnancies with trisomy 21 resulted in live births., Conclusions: Screening for fetal trisomies by cfDNA analysis of maternal blood, contingent on the results of the combined test, can be implemented easily in routine clinical practice. In the high-risk group from the combined test, most but not all women chose cfDNA testing rather than invasive testing. Performance of screening for trisomy 21 was superior by the cfDNA test than by the combined test. However, prenatal detection of trisomies and pregnancy outcome depend not only on performance of screening tests but also on parental choice., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18 and 13 and sex chromosome aneuploidies., Methods: Searches of PubMed, EMBASE and The Cochrane Library were performed to identify all peer-reviewed articles on cfDNA testing in screening for aneuploidies between January 2011, when the first such study was published, and 4 January 2015., Results: In total, 37 relevant studies were identified and these were used for the meta-analysis on the performance of cfDNA testing in screening for aneuploidies. These studies reported cfDNA results in relation to fetal karyotype from invasive testing or clinical outcome. Weighted pooled detection rates (DR) and false-positive rates (FPR) in singleton pregnancies were 99.2% (95% CI, 98.5-99.6%) and 0.09% (95% CI, 0.05-0.14%), respectively, for trisomy 21, 96.3% (95% CI, 94.3-97.9%) and 0.13% (95% CI, 0.07-0.20) for trisomy 18, 91.0% (95% CI, 85.0-95.6%) and 0.13% (95% CI, 0.05-0.26%) for trisomy 13, 90.3% (95% CI, 85.7-94.2%) and 0.23% (95% CI, 0.14-0.34%) for monosomy X and 93.0% (95% CI, 85.8-97.8%) and 0.14% (95% CI, 0.06-0.24%) for sex chromosome aneuploidies other than monosomy X. For twin pregnancies, the DR for trisomy 21 was 93.7% (95% CI, 83.6-99.2%) and the FPR was 0.23% (95% CI, 0.00-0.92%)., Conclusion: Screening for trisomy 21 by analysis of cfDNA in maternal blood is superior to that of all other traditional methods of screening, with higher DR and lower FPR. The performance of screening for trisomies 18 and 13 and sex chromosome aneuploidies is considerably worse than that for trisomy 21., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To examine in a general population the performance of cell-free DNA (cfDNA) testing for trisomies 21, 18 and 13 at 10-11 weeks' gestation and compare it to that of the combined test at 11-13 weeks., Methods: In 2905 singleton pregnancies, prospective screening for trisomies was performed by chromosome-selective sequencing of cfDNA in maternal blood at 10-11 weeks' gestation and by the combined test at 11-13 weeks' gestation., Results: Median maternal age of the study population was 36.9 (range, 20.4-51.9) years. Results from cfDNA analysis were provided for 2851 (98.1%) cases and these were available within 14 days from sampling in 2848 (98.0%) cases. The trisomic status of the pregnancies was determined by prenatal or postnatal karyotyping or clinical examination of the neonates. Of the 2785 pregnancies with a cfDNA result and known trisomic status, cfDNA testing correctly identified all 32 cases with trisomy 21, nine of 10 with trisomy 18 and two of five with trisomy 13, with false-positive rates of 0.04%, 0.19% and 0.07%, respectively. In cases with discordant results between cfDNA testing and fetal karyotype, the median fetal fraction was lower than in those with concordant results (6% vs 11%). Using the combined test, the estimated risk for trisomy 21 was ≥ 1/100 in all trisomic cases and in 4.4% of the non-trisomic pregnancies., Conclusion: The performance of first-trimester cfDNA testing for trisomies 21 and 18 in the general population is similar to that in high-risk pregnancies. Most false-positive and false-negative results from cfDNA testing could be avoided if the a priori risk from the combined test is taken into account in the interpretation of individual risk., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: This study reports on the clinical implementation of cell-free DNA (cfDNA) testing, contingent on the results of the combined test, in screening for fetal trisomies 21, 18 and 13 in two UK National Health Service hospitals. Women with a combined-test risk of ≥ 1:100 (high risk) were offered the options of chorionic villus sampling (CVS), cfDNA testing or no further testing and those with a risk of 1:101 to 1:2500 (intermediate risk) were offered cfDNA or no further testing. The objective of the study was to examine the factors affecting patient decisions concerning their options., Methods: Combined screening was performed in 6651 singleton pregnancies in which the risk for trisomies was high in 260 (3.9%), intermediate in 2017 (30.3%) and low in 4374 (65.8%). Logistic regression analysis was used to determine which factors among maternal characteristics, fetal nuchal translucency thickness (NT) and risk for trisomies were significant predictors of opting for CVS in the high-risk group and opting for cfDNA testing in the intermediate-risk group., Results: In the high-risk group, 104 (40.0%) women opted for CVS; predictors for CVS were increasing fetal NT and increasing risk for trisomies, while the predictor against CVS was being of Afro-Caribbean racial origin (r = 0.366). In the intermediate-risk group, 1850 (91.7%) women opted for cfDNA testing; predictors for cfDNA testing were increasing maternal age, increasing risk for trisomies and university education, while predictors against cfDNA testing were being of Afro-Caribbean racial origin, smoking and being parous (r = 0.105)., Conclusions: This study has identified factors that can influence the decision of women undergoing combined screening in favor of or against CVS and in favor of or against cfDNA testing., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: To report clinical implementation of cell-free DNA (cfDNA) analysis of maternal blood in screening for trisomies 21, 18 and 13 in twin pregnancies and examine variables that could influence the failure rate of the test., Methods: cfDNA testing was performed in 515 twin pregnancies at 10-28 weeks' gestation. The failure rate of the test to provide results was compared with that in 1847 singleton pregnancies, and logistic regression analysis was used to determine which factors among maternal and pregnancy characteristics were significant predictors of test failure., Results: Failure rate of the cfDNA test at first sampling was 1.7% in singletons and 5.6% in twins. Of those with a test result, the median fetal fraction in twins was 8.7% (range, 4.1-30.0%), which was lower than that in singletons (11.7% (range, 4.0-38.9%)). Multivariable regression analysis demonstrated that twin pregnancy, higher maternal weight and conception by in-vitro fertilization provided significant independent prediction of test failure. Follow-up was available in 351 (68.2%) of the twin pregnancies and comprised 334 with euploid fetuses, 12 discordant for trisomy 21 and five discordant for trisomy 18. In all 323 euploid cases with a result, the risk score for each trisomy was < 1:10 000. In 11 of the 12 cases with trisomy 21 and in the five with trisomy 18, the cfDNA test gave a high-risk result, but in one case of trisomy 21, the score was < 1:10 000., Conclusion: In twin pregnancies screening by cfDNA testing is feasible, but the failure rate is higher and detection rate may be lower than in singletons., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To examine potential performance of screening for trisomies by cell-free (cf) DNA testing in maternal blood contingent on results of first-line testing by combinations of fetal translucency thickness (NT), fetal heart rate (FHR), ductus venosus pulsatility index (DV PIV), and serum-free β-human chorionic gonadotropin (β-hCG), pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PLGF) and α-fetoprotein (AFP)., Methods: Performance was estimated for firstly, screening by cfDNA in all pregnancies and secondly, cfDNA testing contingent on results of first-line testing by combinations of ultrasound and biochemical markers., Results: In first-line screening by cfDNA testing, the detection rate for trisomy 21 and trisomies 18 or 13 would be 99 and 96%, respectively, after invasive testing in 1% of the population. In contingent screening, a detection rate of 98% for trisomy 21 and 96% for trisomy 18 or 13, at an invasive testing rate of 0.7%, can be achieved by carrying out cfDNA testing in about 35, 20 and 11% of cases identified by first-line screening with the combined test alone (age, NT, FHR, β-hCG, PAPP-A), the combined test plus PLGF and AFP and the combined test plus PLGF, AFP and DV PIV, respectively., Conclusions: Effective first-trimester screening for trisomies can be achieved by contingent screening incorporating biomarkers and cfDNA testing., (© 2013 S. Karger AG, Basel.)

Objective: To explore the feasibility of routine maternal blood cell-free (cf) DNA testing in screening for trisomies 21, 18 and 13 at 10 weeks' gestation., Method: In this prospective study, women attending The Fetal Medicine Centre in London, UK, between October 2012 and April 2013, with singleton pregnancy and live fetus with CRL 32-45 mm, were screened for trisomies 21, 18 and 13 by cfDNA testing at 10 weeks and the combined test at 12 weeks., Results: cfDNA testing was performed in 1005 singleton pregnancies with a median maternal age of 37 (range, 20-49) years. Risks for trisomies were provided for 957 (95.2%) cases and in 98.0% these were available within 14 days from sampling. In 48 (4.8%) cases no result was provided due to problems with delivery to the laboratory, low fetal fraction or assay failure. Repeat sampling was performed in 40 cases and a result obtained in 27 (67.5%) of these. In 11 cases the risk score for trisomy 21 and in five cases that for trisomy 18 was > 99%, in one the risk for trisomy 13 was 34% and in 968 the risk for each of the three trisomies was < 0.01%. The suspected trisomies were confirmed by karyotyping after chorionic villus sampling (CVS), except in one case of trisomy 18 in which the karyotype was normal. On the basis of the maternal age distribution of the study population, the expected and observed numbers for each of the three trisomies were similar. Both cfDNA and combined testing detected all trisomies, but the estimated false-positive rates (FPR) were 0.1% and 3.4%, respectively., Conclusion: Routine screening for trisomies 21, 18 and 13 by cfDNA testing at 10 weeks is feasible and has a lower FPR than does combined testing, but abnormal results require confirmation by CVS., (Copyright © 2013 ISUOG. Published by John Wiley & Sons, Ltd.)