Abstract：
Analysis of cell-free DNA from maternal blood provides effective screening for trisomy 21 in singleton pregnancies. Data on cell-free DNA screening in twin gestations are promising although limited. In previous twin studies, cell-free DNA screening was primarily performed in the second trimester and many studies did not report chorionicity.
This study aimed to evaluate the screening performance of cell-free DNA for trisomy 21 in twin pregnancies in a large, diverse cohort. A secondary aim was to evaluate screening performance for trisomy 18 and trisomy 13.
This was a retrospective cohort study of twin pregnancies from 17 centers for which cell-free DNA screening was performed from December 2011 to February 2020 by one laboratory using massively parallel sequencing technology. Medical record review was conducted for all newborns and data on the birth outcome, the presence of any congenital abnormalities, phenotypic appearance at birth, and any chromosomal testing that was undertaken in the antenatal or postnatal period were extracted. Cases with a possible fetal chromosomal abnormality with no genetic test results were reviewed by a committee of maternal-fetal medicine geneticists. Cases with a vanishing twin and inadequate follow-up information were excluded. A minimum of 35 confirmed cases of trisomy 21 was required to capture a sensitivity of at least 90% with a prevalence of at least 1.9% with 80% power. Test characteristics were calculated for each outcome.
A total of 1764 samples were sent for twin cell-free DNA screening. Of those, 78 cases with a vanishing twin and 239 cases with inadequate follow-up were excluded, leaving a total of 1447 cases for inclusion in the analysis. The median maternal age was 35 years and the median gestational age at cell-free DNA testing was 12.3 weeks. In total, 81% of the twins were dichorionic. The median fetal fraction was 12.4%. Trisomy 21 was detected in 41 of 42 pregnancies, yielding a detection rate of 97.6% (95% confidence interval, 83.8-99.7). There was 1 false negative and no false positive cases. Trisomy 21 was detected in 38 out of 39 dichorionic twin pregnancies, yielding a detection rate of 97.4% (95% confidence interval, 82.6-99.7). Trisomy 18 was detected in 10 of the 10 affected pregnancies. There was 1 false positive case. Trisomy 13 was detected in 4 of the 5 cases, yielding a detection rate of 80% (95% confidence interval, 11.1-99.2). There was one false negative and no false positive cases. The nonreportable rate was low at 3.9 %.
Cell-free DNA testing is effective in screening for trisomy 21 in twin gestations from the first trimester of pregnancy. Detection of trisomy 21 was high in dichorionic and monochorionic twins, and the nonreportable result rates were low. This study included high numbers of cases of trisomy 18 and 13 when compared with the current literature. Although screening for these conditions in twins seems to be promising, the numbers were too small to make definitive conclusions regarding the screening efficacy for these conditions. It is possible that cell-free DNA testing performance may differ among laboratories and vary with screening methodologies.
This study aimed to evaluate the screening performance of cell-free DNA for trisomy 21 in twin pregnancies in a large, diverse cohort. A secondary aim was to evaluate screening performance for trisomy 18 and trisomy 13.
This was a retrospective cohort study of twin pregnancies from 17 centers for which cell-free DNA screening was performed from December 2011 to February 2020 by one laboratory using massively parallel sequencing technology. Medical record review was conducted for all newborns and data on the birth outcome, the presence of any congenital abnormalities, phenotypic appearance at birth, and any chromosomal testing that was undertaken in the antenatal or postnatal period were extracted. Cases with a possible fetal chromosomal abnormality with no genetic test results were reviewed by a committee of maternal-fetal medicine geneticists. Cases with a vanishing twin and inadequate follow-up information were excluded. A minimum of 35 confirmed cases of trisomy 21 was required to capture a sensitivity of at least 90% with a prevalence of at least 1.9% with 80% power. Test characteristics were calculated for each outcome.
A total of 1764 samples were sent for twin cell-free DNA screening. Of those, 78 cases with a vanishing twin and 239 cases with inadequate follow-up were excluded, leaving a total of 1447 cases for inclusion in the analysis. The median maternal age was 35 years and the median gestational age at cell-free DNA testing was 12.3 weeks. In total, 81% of the twins were dichorionic. The median fetal fraction was 12.4%. Trisomy 21 was detected in 41 of 42 pregnancies, yielding a detection rate of 97.6% (95% confidence interval, 83.8-99.7). There was 1 false negative and no false positive cases. Trisomy 21 was detected in 38 out of 39 dichorionic twin pregnancies, yielding a detection rate of 97.4% (95% confidence interval, 82.6-99.7). Trisomy 18 was detected in 10 of the 10 affected pregnancies. There was 1 false positive case. Trisomy 13 was detected in 4 of the 5 cases, yielding a detection rate of 80% (95% confidence interval, 11.1-99.2). There was one false negative and no false positive cases. The nonreportable rate was low at 3.9 %.
Cell-free DNA testing is effective in screening for trisomy 21 in twin gestations from the first trimester of pregnancy. Detection of trisomy 21 was high in dichorionic and monochorionic twins, and the nonreportable result rates were low. This study included high numbers of cases of trisomy 18 and 13 when compared with the current literature. Although screening for these conditions in twins seems to be promising, the numbers were too small to make definitive conclusions regarding the screening efficacy for these conditions. It is possible that cell-free DNA testing performance may differ among laboratories and vary with screening methodologies.
摘要：
背景：对母体血液中的无细胞DNA的分析为单胎妊娠中的21三体提供了有效的筛查。双胞胎中无细胞DNA筛查的数据虽然有限，但仍有希望。在先前的双胞胎研究中，无细胞DNA筛选主要在妊娠中期进行，许多研究没有报告绒毛膜。
目的：我们试图评估无细胞DNA在双胎妊娠中的筛选性能，多样化的队列。次要目的是评估18三体和13三体的筛选性能。
方法：回顾性队列研究来自17个中心的双胎妊娠，从2011年12月2日至2020年2月由一个实验室使用大规模平行测序技术进行无细胞DNA筛查。对所有新生儿进行医疗记录审查，包括出生结果，任何先天性异常的存在，出生时的表型外观以及在产前或产后进行的任何染色体检测。母胎医学（MFM）遗传学家委员会对可能存在胎儿染色体异常且没有基因检测结果的病例进行了审查。排除双胞胎消失且随访信息不足的病例。至少需要35例确诊的T21病例才能捕获至少90％的灵敏度，至少1.9％的患病率和80％的功率。计算每个结果的测试特征。
结果：总共1764个样本被送去进行无孪生细胞DNA筛选。排除了78例双胞胎消失的病例和239例随访不足的病例，共1447例纳入分析。孕妇的中位年龄为35岁，无细胞DNA检测的中位孕龄为12.3周。81％的双胞胎是二甲虫。胎儿分数中位数为12.4%。在42例妊娠中有41例检测到21三体，检出率为97.6%(95%CI83.8-99.7)。有一个假阴性，没有假阳性病例。在39例双胎双胎妊娠中，有38例检测到21三体，检出率为97.4％（95％CI82.6-99.7）。在10个受影响的怀孕中，有10个检测到18三体。有一个假阳性病例。在5例中的4例中检测到13三体，检出率为80％（95％CI11.1-99.2）。有一个假阴性，没有假阳性病例。不可报告率很低，为3.9%。
结论：无细胞DNA可有效筛查从妊娠前三个月开始的双胎妊娠21三体。在双绒毛膜和单绒毛膜双胞胎中，21三体的检出率很高，不可报告的结果率很低。与目前的文献相比，这项研究包括大量的18和13三体病例。尽管在双胞胎中筛查这些疾病似乎很有希望，这些数字太小,无法就这些疾病的筛查效果得出明确的结论.无细胞DNA性能可能在实验室之间有所不同，并且随筛选方法而变化。
目的：我们试图评估无细胞DNA在双胎妊娠中的筛选性能，多样化的队列。次要目的是评估18三体和13三体的筛选性能。
方法：回顾性队列研究来自17个中心的双胎妊娠，从2011年12月2日至2020年2月由一个实验室使用大规模平行测序技术进行无细胞DNA筛查。对所有新生儿进行医疗记录审查，包括出生结果，任何先天性异常的存在，出生时的表型外观以及在产前或产后进行的任何染色体检测。母胎医学（MFM）遗传学家委员会对可能存在胎儿染色体异常且没有基因检测结果的病例进行了审查。排除双胞胎消失且随访信息不足的病例。至少需要35例确诊的T21病例才能捕获至少90％的灵敏度，至少1.9％的患病率和80％的功率。计算每个结果的测试特征。
结果：总共1764个样本被送去进行无孪生细胞DNA筛选。排除了78例双胞胎消失的病例和239例随访不足的病例，共1447例纳入分析。孕妇的中位年龄为35岁，无细胞DNA检测的中位孕龄为12.3周。81％的双胞胎是二甲虫。胎儿分数中位数为12.4%。在42例妊娠中有41例检测到21三体，检出率为97.6%(95%CI83.8-99.7)。有一个假阴性，没有假阳性病例。在39例双胎双胎妊娠中，有38例检测到21三体，检出率为97.4％（95％CI82.6-99.7）。在10个受影响的怀孕中，有10个检测到18三体。有一个假阳性病例。在5例中的4例中检测到13三体，检出率为80％（95％CI11.1-99.2）。有一个假阴性，没有假阳性病例。不可报告率很低，为3.9%。
结论：无细胞DNA可有效筛查从妊娠前三个月开始的双胎妊娠21三体。在双绒毛膜和单绒毛膜双胞胎中，21三体的检出率很高，不可报告的结果率很低。与目前的文献相比，这项研究包括大量的18和13三体病例。尽管在双胞胎中筛查这些疾病似乎很有希望，这些数字太小,无法就这些疾病的筛查效果得出明确的结论.无细胞DNA性能可能在实验室之间有所不同，并且随筛选方法而变化。
