First-Trimester Contingent Screening for Trisomies 21, 18 and 13 by Biomarkers and Maternal Blood Cell-Free DNA Testing

Abstract

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.

Analysis of Cell-Free DNA in Maternal Blood in Screening for Aneuploidies: Meta-Analysis

“…We estimated that if cfDNA testing of maternal blood was offered as a first-line method of screening to all pregnancies about 99% of fetuses with trisomy 21 and 95% with trisomies 13 and 18 could be detected at an overall invasive testing rate of 1% [74]. …”

“…However, this proportion can be reduced to about 17% if first-line screening includes serum PLGF and AFP, in addition to fetal NT, FHR and serum-free β-hCG and PAPP-A [74]. A further reduction in the need for cfDNA testing to less than 10%, without affecting the overall performance of screening, can potentially be achieved by a first-line method of screening which includes ductus venosus pulsatility index, in addition to fetal NT, FHR and serum-free β-hCG, PAPP-A, PLGF and AFP [74]. …”

Cell-Free DNA Analysis for Trisomy Risk Assessment in First-Trimester Twin Pregnancies

“…In twin pregnancies, as in singletons, there are essentially two options in the introduction of cfDNA testing in such a way as to retain the advantages of the 11- to 13-week scan [15,27]. One option is to carry cfDNA testing in all women at 10 weeks' gestation followed by a scan at 12 weeks; in patients with a high-risk score from cfDNA testing, invasive diagnostic testing and selective fetocide can be carried out in the first trimester.…”

“…This approach retains the major advantages of cfDNA testing in increasing the detection rate of trisomies and decreasing the false positive rate, but at considerably lower cost than offering the test to the whole population [27]. The disadvantage of this approach, arising from delay or failure to obtain a result, is the resultant shift in diagnosis from the first to the second trimester.…”

Clinical Perspective of Cell-Free DNA Testing for Fetal Aneuploidies

“…The first option is to offer cfDNA testing routinely to the whole population. The estimated performance of such an approach is the detection of about 99% of fetuses with trisomy 21 and 95% with trisomies 13 and 18 at an overall invasive testing rate of 1% [34]. In this strategy it would be best to carry out cfDNA testing at 10 weeks' gestation, as explained above for private patients.…”