Cell-free DNA screening for trisomy 21 in twin pregnancy: a large multicenter cohort study.
Academic Article
Overview
abstract
BACKGROUND: Analysis of cell-free DNA from maternal blood provides effective screening for trisomy 21 in singleton pregnancies. Data on cell-free DNA screening in twins are promising though limited. In previous twin studies cell-free DNA screening was primarily performed in the second trimester and many studies did not report chorionicity. OBJECTIVE: We sought 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. STUDY DESIGN: Retrospective cohort study of twin pregnancies from 17 centers with cell-free DNA screening performed from 12/2011-2/2020 by one lab using massively parallel sequencing technology. Medical record review was undertaken for all newborns including birth outcome, the presence of any congenital abnormalities, phenotypic appearance at birth and any chromosomal testing undertaken in the antenatal or postnatal period. Cases with a possible fetal chromosomal abnormality with no genetic test results were reviewed by a committee of Maternal Fetal Medicine (MFM) geneticists. Cases with a vanishing twin and inadequate follow up information were excluded. A minimum of 35 confirmed cases of T21 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. RESULTS: A total of 1764 samples were sent for twin cell-free DNA screening. Seventy-eight 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. Eighty-one percent of the twins were dichorionic. The median fetal fraction was 12.4%. Trisomy 21 was detected in 41 out of 42 pregnancies yielding a 97.6% (95% CI 83.8 - 99.7) detection rate. There was one false negative and no false positive cases. Trisomy 21 was detected in 38 out of 39 dichorionic twin pregnancies yielding a 97.4% (95% CI 82.6-99.7) detection rate. Trisomy 18 was detected in 10 out of the 10 affected pregnancies. There was one false positive case. Trisomy 13 was detected in 4 out of the 5 cases yielding an 80% (95% CI 11.1 - 99.2) detection rate. There was one false negative and no false positive cases. The non-reportable rate was low at 3.9 %. CONCLUSION: Cell-free DNA is effective in screening for trisomy 21 in twin gestations beginning in the first trimester of pregnancy. Detection for trisomy 21 was high in dichorionic and monochorionic twins and the non-reportable result rates were low. This study included high numbers of cases of trisomy 18 and 13 compared to the current literature. Although screening for these conditions in twins appears to be promising, the numbers were too small to make definitive conclusions regarding screening efficacy for these conditions. It is possible that cell-free DNA performance may differ among labs and vary with screening methodologies.
