Study Finds Sequential Screening Provides Better Test Performance than Cell Free DNA When Considering all Fetal Chromosomal Abnormalities

SAN DIEGO (Feb. 2, 2015)—In a study to be presented on Feb. 5 in an oral plenary session at 8 a.m. PST, at the Society for Maternal-Fetal Medicine’s annual meeting, The Pregnancy Meeting™, in San Diego, researchers will report that cell free DNA analysis is less effective than sequential screening as primary testing for fetal chromosomal abnormalities.

The study, titled Cell free DNA Analysis vs. Sequential Screening as Primary Testing Considering Chromosomal Abnormalities, compared sequential screening to cell free DNA for detection of all fetal chromosomal abnormalities in a general prenatal cohort.

The study discusses some of the complexities of cell free DNA screening when implemented in large populations. Although cell free DNA can very precisely detect Down syndrome and a few other serious chromosome abnormalities (as well as fetal sex), there are two limitations that are important. One is that cell free DNA screens for a very limited panel of abnormalities, as compared to current screening, which is able to determine that there is an increase in risk in the presence of a very broad array of fetal abnormalities, including many different chromosome problems in addition to the common conditions.

Secondly, sequencing of fetal DNA is complex, and requires that a minimum amount of fetal DNA be present in the mother’s blood. In those patients with low fetal DNA or failed sequencing interpretation, the risk of aneuploidy (chromosome abnormality) is higher, so some cases of aneuploidy will remain undetected. In this study, the investigators considered these two characteristics in analyzing cell free DNA testing in comparison to the current screen as implemented in the California Prenatal Screening Program.

In a cohort of 450,000 women, the California PNS detected 82 percent of chromosome abnormalities at a 4.9 percent screen positive rate. It was calculated that cell free DNA would have detected approximately 68 percent at a one percent screen positive rate. If all the patients with failed cell free DNA tests were flagged as “high risk,” the detection rate would increase to 78 percent but the false positive rate would be 5.5 percent.

“Overall, when considering all chromosome abnormalities and including those cases with no test result, sequential screening has better test performance than cell free DNA,” stated Mary Norton, M.D. with the University of California, San Francisco, Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences. Norton will present the study.

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A copy of the abstract is available at and below. For interviews please contact Vicki Bendure at 202-374-9259 (cell).
The Society for Maternal-Fetal Medicine (est. 1977) is the premiere membership organization for obstetricians/gynecologists who have additional formal education and training in maternal-fetal medicine. The society is devoted to reducing high-risk pregnancy complications by sharing expertise through continuing education to its 2,000 members on the latest pregnancy assessment and treatment methods. It also serves as an advocate for improving public policy, and expanding research funding and opportunities for maternal-fetal medicine. The group hosts an annual meeting in which groundbreaking new ideas and research in the area of maternal-fetal medicine are shared and discussed. For more information visit

Abstract 2: Cell free DNA Analysis vs Sequential Screening as Primary Testing Considering All Fetal Chromosomal Abnormalities

Authors: Mary Norton1, Ronald Wapner2, Miriam Kuppermann1, Laura Jelliffe-Pawlowski3, Robert Currier3
1University of California, San Francisco, Division of Maternal Fetal Medicine, Department of
Obstetrics, Gynecology and Reproductive Sciences, San Francisco, CA, 2Columbia University
Medical Center, Obstetric and Gynecology, New York, NY, 3California Department of Public
Health, Genetic Disease Screening Program, Richmond, CA

Objective: To compare sequential screening and cell free DNA (cfDNA) for detection of all
fetal chromosomal abnormalities in a general prenatal cohort.

Study Design: The detection (DR) and false positive rates of sequential screening for all
chromosome abnormalities were determined in the CA Prenatal Screening Program (PNS) and
compared to estimated DR and FPR of cfDNA. Cytogenetic abnormalities were collected by
state mandated reporting of all chromosome abnormalities diagnosed prenatally or at age <1 y.
DR and FPR were calculated for all chromosome abnormalities; these were categorized as
detectable (T13,18,21,sex chromosomal aneuploidy (SCA), or not detectable (i.e.rare
aneuploidies, large deletions/duplications) by cfDNA. DR and FPR for cfDNA were abstracted
from published literature; per recent reports, “no results” cases were considered high-risk (screen
positive) for T13,18 and triploidy. Lab approaches with and without fetal fraction (FF)
measurement were compared (table); those reporting no result when FF<4% were considered to
have >99% DR for T13/18/21, 93% for SCA, and no results in 3-8%; those that do not require
FF>4% have DR of 85% and 95% for T13 and 18, 93% for SCA, >99% for T21, and no results
in 1%.

Results: Of 452,901 women with due dates from Aug 2009 to Dec 2012, 2575 had a fetal
chromosomal abnormality and 2101 had positive sequential screening for a DR of 81.6%, and
FPR of 4.11%. 1883 (73%) chromosomal abnormalities were potentially detectable with cfDNA.
For labs using FF, estimated DR is 72% and FPR is 3.5-8%; for labs not using FF, estimated DR
is 70% and FPR is 1.5%.

Conclusion: For primary screening, cfDNA provides lower DR than sequential screening if
considering detection of all chromosomal abnormalities. Flagging no results cfDNA cases as
high-risk improves cfDNA detection but increases FPR. Before adopting cfDNA as primary
population screening, evaluation of the implications for detection of all chromosomal
abnormalities, and the benefits of incorporating FF is needed.
DR and FPR for detection of all chromosome abnormalities for sequential screening vs cfDNA
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