Fetal Medicine Unit, Department of Obstetrics and Gynaecology, and Twins Trust Centre for Research and Clinical Excellence, St George's University Hospitals NHS Foundation Trust, London, United Kingdom; Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George's, University of London, London, United Kingdom.
mOm Incubators Ltd, London, United Kingdom (formerly Premaitha Health, Manchester, United Kingdom).
Am J Obstet Gynecol. 2021 Jul;225(1):79.e1-79.e13. doi: 10.1016/j.ajog.2021.01.005. Epub 2021 Jan 15.
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 100% for trisomy 13 (n=1; 95% confidence interval, 3-100). The corresponding false-positive rates were 0% (95% confidence interval, 0-0.39), 0.10% (95% confidence interval, 0-0.58), and 0% (95% confidence interval, 0-0.39), respectively. By combining data from our study with the 11 studies identified by literature search, the detection rate for trisomy 21 was 95% (n=74; 95% confidence interval, 90-99) and the false-positive rate was 0.09% (n=5598; 95% confidence interval, 0.03-0.19). The corresponding values for trisomy 18 were 82% (n=22; 95% confidence interval, 66-93) and 0.08% (n=4869; 95% confidence interval, 0.02-0.18), respectively. There were 5 cases of trisomy 13 and 3881 non-trisomy 13 pregnancies, resulting in a computed average detection rate of 80% and a false-positive rate of 0.13%.
This large multicenter study confirms that cell-free DNA testing is the most accurate screening test for trisomy 21 in twin pregnancies, with screening performance similar to that in singletons and very low failure rates (0.31%). The predictive accuracy for trisomies 18 and 13 may be less. However, given the low false-positive rate, offering first-line screening with cell-free DNA to women with twin pregnancy is appropriate in our view and should be considered a primary screening test for trisomy 21 in twins.
在单胎妊娠中，研究表明，游离于母体外周血中的胎儿 DNA 检测唐氏综合征（21 三体、18 三体和 13 三体）的检出率高、假阳性率低。与单胎妊娠相比，非侵入性产前检测在双胎妊娠中具有更大的潜在优势，尤其是侵入性检测的需求降低，从而导致胎儿丢失率降低。然而，一些组织不建议在双胎妊娠中使用游离 DNA，并呼吁开展更大规模的前瞻性研究。
针对这一情况，我们开展了一项大型前瞻性多中心研究，旨在建立游离 DNA 在双胎妊娠中检测三种常见三体的筛查性能。此外，我们将我们的数据与已发表的研究报告中的数据相结合，以获得最佳的筛查性能估计值。
这是一项前瞻性多中心、盲法研究，评估了游离于母体外周血中的胎儿 DNA 在双胎妊娠中检测胎儿三体的筛查性能。该研究在英国的 6 家胎儿医学中心进行。主要结局是使用下一代测序（IONA 测试）进行游离 DNA 的筛查性能和检测失败率。在常规筛查试验时或之后采集母血。在入组时、妊娠期间的任何相关侵入性检测时以及分娩后直至出院时收集数据。对所有新生儿进行前瞻性详细的结局评估。本研究按照诊断准确性研究报告标准进行。还于 2020 年 6 月 6 日对文献检索（MEDLINE、Embase、CENTRAL、Cochrane 图书馆和 ClinicalTrials.gov）中确定的研究数据和我们的数据进行了汇总分析。
共招募了 1003 例双胎妊娠女性，961 例（95.8%）完成了完整的数据随访和参照数据，276 例为单绒毛膜性，685 例为双绒毛膜性。检测失败率为 0.31%。平均胎儿分数为 12.2%（范围 3%-36%）；所有 9 例胎儿分数为 3%的样本均提供了有效结果。21 三体或 13 三体均无假阳性或假阴性结果，而 18 三体有 1 例假阴性和 1 例假阳性结果。IONA 测试对 21 三体的检出率为 100%（n=13；95%置信区间，75%-100），18 三体为 0%（n=1；95%置信区间，0%-98），13 三体为 100%（n=1；95%置信区间，3%-100）。相应的假阳性率分别为 0%（95%置信区间，0%-0.39）、0.10%（95%置信区间，0%-0.58）和 0%（95%置信区间，0%-0.39）。通过将我们的研究数据与文献检索中确定的 11 项研究的数据相结合，21 三体的检出率为 95%（n=74；95%置信区间，90%-99），假阳性率为 0.09%（n=5598；95%置信区间，0.03%-0.19）。18 三体的检出率分别为 82%（n=22；95%置信区间，66%-93）和 0.08%（n=4869；95%置信区间，0.02%-0.18）。13 三体有 5 例，非 13 三体有 3881 例，计算得出的平均检出率为 80%，假阳性率为 0.13%。
这项大型多中心研究证实，游离 DNA 检测是双胎妊娠中检测 21 三体最准确的筛查试验，其筛查性能与单胎妊娠相似，且检测失败率非常低（0.31%）。18 三体和 13 三体的预测准确性可能较低。然而，鉴于低的假阳性率，我们认为在双胎妊娠妇女中使用游离 DNA 进行一线筛查是合适的，应将其视为双胎妊娠 21 三体的主要筛查试验。
