Maternal Plasma DNA Screening for Fetal Trisomies 21 and 18 May Reduce the Need for Invasive Follow-up Testing Compared to Standard Aneuploidy Screening

EBM Focus - Volume 9, Issue 10

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Reference: N Engl J Med 2014 Feb 27;370(9):799 (level 2 [mid-level] evidence)

Screening for chromosomal abnormalities is now part of standard prenatal care, and the American College of Obstetricians and Gynecologists currently recommends screening unselected women with both nuchal translucency and biochemical markers (Obstet Gynecol 2007 Jan;109(1):217). Advances in rapid DNA sequencing and sequence analysis have led to the development of new technologies for prenatal screening, including screening for chromosomal abnormalities such as trisomy 21 (Down syndrome) and trisomy 18 (Edward syndrome). Cell-free DNA testing using massively parallel sequencing of maternal plasma has recently been shown to have high predictive performance for detection of fetal trisomy in study populations involving karyotypes associated with very high risk of aneuploidy (Genet Med 2011 Nov;13(11):913, Obstet Gynecol 2012 May;119(5):890). Now, a validation cohort study evaluates the prognostic performance of massively parallel sequencing cell-free DNA testing and standard aneuploidy screening for fetal trisomies in a general obstetric population.

A total of 2,042 adult women (mean age 30 years) with singleton pregnancies of gestational age ≥ 8 weeks had cell-free DNA testing and standard aneuploidy screening for detection of fetal trisomies 21, 18, and 13. Cell-free DNA testing consisted of massively parallel sequencing of maternal plasma cell-free DNA from 10-mL sample of peripheral venous blood taken during the first, second, or third trimester. Standard aneuploidy screening included assays for first or second trimester serum markers, either with or without nuchal translucency measurement from fetal ultrasound. The reference standard was newborn physical exam, or karyotype analysis in the case of nonlive birth. Overall, 1,914 women without loss to follow-up and having results for karyotype analysis, cell-free DNA testing, and standard aneuploidy screening were included in the analysis.

There were a total of 5 cases (0.3%) of trisomy 21 and 2 cases (0.1%) of trisomy 18 by reference standard. For detection of trisomy 21, cell-free DNA testing had sensitivity 100%, specificity 99.7%, positive predictive value 45.5%, and negative predictive value 100%. The corresponding performance measures for standard aneuploidy screening were sensitivity 100%, specificity 96.4%, positive predictive value 4.2%, and negative predictive value 100%. Similarly, for detection of trisomy 18, cell-free DNA testing had sensitivity 100%, specificity 99.8%, positive predictive value 40%, and negative predictive value 100%. The corresponding performance measures for standard aneuploidy screening were sensitivity 100%, specificity 99.4%, positive predictive value 8.3%, and negative predictive value 100%. For both trisomy 21 and trisomy 18, cell-free DNA testing was associated with significantly increased specificity and positive predictive value compared to standard aneuploidy screening.

The results of this study confirm that a negative result with cell-free DNA testing using massively parallel sequencing of maternal plasma is associated with a greatly reduced risk of fetal trisomy 21 and trisomy 18 in a general obstetric population. The positive predictive values for detecting each fetal trisomy were low for both cell-free DNA testing and standard aneuploidy screening, highlighting the need for more invasive confirmatory testing (such as amniocentesis) for diagnosing these conditions in the case of a positive result. However, cell-free DNA testing was associated with significantly higher sensitivity and positive predictive values for both fetal trisomies, meaning that fewer women would be needlessly discomforted by a false positive result, and fewer would require invasive testing for confirmation.

For more information see the Screening and monitoring during pregnancy, Down syndrome, and Trisomy 18 topics in Dynamed.


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