False-Positive Rate in First-Trimester Screening Based on Ultrasound and Cell-Free DNA versus First-Trimester Combined Screening with Additional Ultrasound Markers

ABSTRACT Prenatal screening for fetal aneuploidies has been focused on mainly Down syndrome in the last 40 years. The method of screening has changed from maternal age in the 1970s, with a detection rate of 30 and 5% false positive rate (FPR), to a combination of maternal age and second-trimester serum biochemical markers (triple test and quadruple test) in the 1980s and 1990s, with 60 to 75% detection rate and 5% false positive rate (FPR). Following this, the era of first trimester screening for Down syndrome has started with the clinical implementation of fetal nuchal translucency screening. The combination of maternal age, NT thickness and serum free beta-human chorionic gonadotropin (â-hCG) and pregnancy-associated plasma protein A (PAPP-A) in the first trimester has yielded a 90% detection rate with a 5% FPR. Starting from the year 2008, studies have shown that the performance of screening may be improved by analysis of cell-free deoxyribonucleic acid (DNA) (cfDNA) in maternal blood. Several studies in the last few years have reported the clinical validation of cell free fetal DNA test in the maternal serum in screening for trisomies 21, 18, and 13 and sex chromosome aneuploidies. Its widespread use is limited by the relatively high cost of the test and the lack of consensus about the optimal way for its clinical implementation. Until the optimal way of incorporating cfDNA into the clinical practice gets identified, it would be wise not to substitute cfDNA testing in place of first-trimester screening for fetal defects and other major complications of pregnancy. Furthermore, it would be preferable for clinicians managing individual patients not to counsel them for their result as positive or negative, rather the clinicians should use the risk estimate from the first-line method of screening as the prior risk and modify this by the appropriate positive or negative likelihood ratio from the cfDNA test. How to cite this article Sen C, Api O, Yayla M, Goynumer G. Cell-free DNA Testing: Where are We now? Donald School J Ultrasound Obstet Gynecol 2016;10(2):172-177.

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DEGUM, ÖGUM, SGUM and FMF Germany Recommendations for the Implementation of First-Trimester Screening, Detailed Ultrasound, Cell-Free DNA Screening and Diagnostic Procedures

Ultraschall in der Medizin - European Journal of Ultrasound ◽

10.1055/a-0631-8898 ◽

2018 ◽

Vol 40 (02) ◽

pp. 176-193 ◽

Cited By ~ 10

Author(s):

Peter Kozlowski ◽

Tilo Burkhardt ◽

Ulrich Gembruch ◽

Markus Gonser ◽

Christiane Kähler ◽

...

Keyword(s):

Genetic Analysis ◽

False Positive ◽

Diagnostic Procedure ◽

First Trimester ◽

First Trimester Screening ◽

Prenatal Counseling ◽

Cell Free Dna ◽

Predictive Values ◽

Free Dna ◽

Trimester Screening

AbstractFirst-trimester screening between 11 + 0 and 13 + 6 weeks with qualified prenatal counseling, detailed ultrasound, biochemical markers and maternal factors has become the basis for decisions about further examinations. It detects numerous structural and genetic anomalies. The inclusion of uterine artery Doppler and PlGF screens for preeclampsia and fetal growth restriction. Low-dose aspirin significantly reduces the prevalence of severe preterm eclampsia. Cut-off values define groups of high, intermediate and low probability. Prenatal counseling uses detection and false-positive rates to work out the individual need profile and the corresponding decision: no further diagnosis/screening – cell-free DNA screening – diagnostic procedure and genetic analysis. In pre-test counseling it must be recognized that the prevalence of trisomy 21, 18 or 13 is low in younger women, as in submicroscopic anomalies in every maternal age. Even with high specificities, the positive predictive values of screening tests for rare anomalies are low. In the general population trisomies and sex chromosome aneuploidies account for approximately 70 % of anomalies recognizable by conventional genetic analysis. Screen positive results of cfDNA tests have to be proven by diagnostic procedure and genetic diagnosis. In cases of inconclusive results a higher rate of genetic anomalies is detected. Procedure-related fetal loss rates after chorionic biopsy and amniocentesis performed by experts are lower than 1 to 2 in 1000. Counseling should include the possible detection of submicroscopic anomalies by comparative genomic hybridization (array-CGH). At present, existing studies about screening for microdeletions and duplications do not provide reliable data to calculate sensitivities, false-positive rates and positive predictive values.

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Ductus venosus pulsatility index measurement reduces the false-positive rate in first-trimester screening

Ultrasound in Obstetrics and Gynecology ◽

10.1002/uog.7706 ◽

2010 ◽

Vol 36 (6) ◽

pp. 661-667 ◽

Cited By ~ 16

Author(s):

E. Timmerman ◽

K. Oude Rengerink ◽

E. Pajkrt ◽

B. C. Opmeer ◽

J. A. M. van der Post ◽

...

Keyword(s):

False Positive ◽

Pulsatility Index ◽

False Positive Rate ◽

First Trimester ◽

Ductus Venosus ◽

First Trimester Screening ◽

Index Measurement ◽

Positive Rate ◽

Trimester Screening

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False positive rate in first trimester screening based on ultrasound and cfDNA vs. first-trimester combined screening with additional ultrasound markers

10.1055/s-0038-1671187 ◽

2018 ◽

Author(s):

KO Kagan ◽

P Wagner ◽

H Abele ◽

M Hoopmann

Keyword(s):

False Positive ◽

False Positive Rate ◽

First Trimester ◽

First Trimester Screening ◽

Positive Rate ◽

Trimester Screening

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610: Actual rates of recommended diagnostic testing after first trimester screening vs. same-day screening by cell free DNA

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2015.10.655 ◽

2016 ◽

Vol 214 (1) ◽

pp. S326 ◽

Cited By ~ 1

Author(s):

Arin Buresch ◽

Mara Rosner ◽

Barrie Suskin ◽

Francine Einstein ◽

Emnonila Bircaj ◽

...

Keyword(s):

Diagnostic Testing ◽

First Trimester ◽

First Trimester Screening ◽

Cell Free Dna ◽

Free Dna ◽

Trimester Screening

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SIGNIFICANCE OF LOW MATERNAL SERUM Β-HCG LEVELS IN THE ASSESSMENT OF THE RISK OF ATYPICAL CHROMOSOMAL ABNORMALITIES

Fetal Diagnosis and Therapy ◽

10.1159/000521345 ◽

2021 ◽

Author(s):

Robin Wijngaard ◽

Elena Casals ◽

Imma Mercadé ◽

Javier Laguna ◽

Irene Madrigal ◽

...

Keyword(s):

Chromosomal Abnormalities ◽

First Trimester ◽

Maternal Serum ◽

First Trimester Screening ◽

Cell Free Dna ◽

Substantial Impact ◽

Free Dna ◽

Trimester Screening ◽

Β Hcg ◽

The Impact

Introduction: The introduction of prenatal cell-free DNA as a screening test has surpassed traditional combined first-trimester screening (cFTS) in the detection of common trisomies. However, its current limitation in detecting only common trisomies is affecting the diagnostic yield for other clinically significant chromosomal abnormalities. Methods: In efforts to optimize the detection of fetuses with genetic abnormalities, we have analyzed the relationship between the cFTS risk score and biomarkers with atypical chromosomal abnormalities. Furthermore, we have evaluated the impact of prenatal cell-free DNA screening on the detection of chromosomal abnormalities in our population. For these purposes, we performed a retrospective study of 877 singleton pregnancies who underwent chromosomal microarray analysis (CMA) between 2013 to 2020 and for whom first-trimester screening data were available. Results: The results demonstrated that low levels of free beta human chorionic gonadotropin (β-hCG) (≤ 0.37 MoM) and increased fetal nuchal translucency (NT) (≥ 3.5mm) were statistically associated with the presence of atypical chromosomal abnormalities. In fact, the risk of pathogenic CMA results increased from 6% to 10% when fetal NT was increased and from 6% to 20% when a low serum β-hCG level was detected in the high-risk cFTS group. Moreover, our results showed that altered serum levels of β-hCG can have a substantial impact on the early detection of clinically relevant copy number variants. Discussion/Conclusion: Traditional cFTS can potentially identify a substantial proportion of atypical chromosomal aberrations, and women with increased NT or low maternal serum β-hCG levels are at increased risk of having pathogenic CMA results. Our results may help clinicians and women decide whether invasive testing or prenatal cell-free DNA screening testing are more appropriate for each situation.

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New screen on the block: non-invasive prenatal testing for fetal chromosomal abnormalities

Journal of Primary Health Care ◽

10.1071/hc16055 ◽

2017 ◽

Vol 9 (4) ◽

pp. 248 ◽

Cited By ~ 1

Author(s):

Sara Filoche ◽

Beverley Lawton ◽

Angela Beard ◽

Anthony Dowell ◽

Peter Stone

Keyword(s):

False Positive ◽

Chromosomal Abnormalities ◽

False Positive Rate ◽

Prenatal Testing ◽

Diagnostic Procedures ◽

First Trimester ◽

Maternal Blood ◽

Non Invasive ◽

Positive Rate ◽

Trimester Screening

ABSTRACT Non-invasive prenatal testing (NIPT) is a new screen for fetal chromosomal abnormalities. It is a screening test based on technology that involves the analysis of feto-placental DNA that is present in maternal blood. This DNA is then analysed for abnormalities of specific chromosomes (eg 13, 18, 21, X, Y). NIPT has a much higher screening capability for chromosomal abnormalities than current combined first trimester screening, with ~99% sensitivity for trisomy 21 (Down syndrome) and at least a 10-fold higher positive predictive value. The low false-positive rate (1–3%) is one of the most advertised advantages of NIPT. In practice, this could lead to a significant reduction in the number of false-positive tests and the need for invasive diagnostic procedures. NIPT is now suitable for singleton and twin pregnancies and can be performed from ~10 weeks in a pregnancy. NIPT is not currently publicly funded in most countries. However, the increasing availability of NIPT commercially will likely lead to an increase in demand for this as a screening option. Given the high numbers of women who visit a general practitioner (GP) in their first trimester, GPs are well-placed to also offer NIPT as a screening option. A GP’s role in facilitating access to this service will likely be crucial in ensuring equity in access to this technology, and it is important to ensure that they are well supported to do so.

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First Trimester Screening for Common Trisomies and Microdeletion 22q11.2 Syndrome Using Cell-Free DNA: A Prospective Clinical Study

Fetal Diagnosis and Therapy ◽

10.1159/000510069 ◽

2020 ◽

pp. 1-11

Author(s):

Karl Oliver Kagan ◽

Markus Hoopmann ◽

Theresa Pfaff ◽

Natalia Prodan ◽

Philipp Wagner ◽

...

Keyword(s):

Clinical Study ◽

First Trimester ◽

Prospective Clinical Study ◽

First Trimester Screening ◽

Cell Free Dna ◽

Free Dna ◽

Trimester Screening ◽

Microdeletion 22Q11.2

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First-trimester screening-biomarkers and cell-free DNA

The Journal of Maternal-Fetal & Neonatal Medicine ◽

10.1080/14767058.2019.1698031 ◽

2019 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Ioan Suciu ◽

Slavyana Galeva ◽

Samira Abdel Azim ◽

Lucian Pop ◽

Oana Toader

Keyword(s):

First Trimester ◽

First Trimester Screening ◽

Cell Free Dna ◽

Free Dna ◽

Trimester Screening

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Combined First-Trimester Screening in Northern Finland: Experiences of the First Ten Years

Clinical Medicine Insights Reproductive Health ◽

10.4137/cmrh.s14958 ◽

2014 ◽

Vol 8 ◽

pp. CMRH.S14958

Author(s):

Merilainen Anna ◽

Peuhkurinen Sini ◽

Honkasalo Timppa ◽

Laitinen Paivi ◽

Kokkonen Hannaleena ◽

...

Keyword(s):

Detection Rate ◽

False Positive Rate ◽

Down's Syndrome ◽

Down’S Syndrome ◽

First Trimester ◽

First Trimester Screening ◽

Invasive Procedures ◽

Screening Performance ◽

Positive Rate ◽

Trimester Screening

Objective To evaluate the efficacy of first trimester combined screening for Down's syndrome in Northern Finland during the first 10 years of practice. Methods During 1 January 2002 to 31 December 2011, 47,896 women participated voluntarily in combined screening during first trimester. The risk cutoff was 1:250. The study period was divided into two time periods; 2002-2006 and 2007-2011. Results During the first half of the study period, the detection rate (DR) was 77.3% with a 4.9% false-positive rate (FPR). During the latter half, the DR was 77.1% with a 2.8% FPR. Conclusions An important issue is the number of invasive procedures needed to detect one case of Down's syndrome. The screening performance improved markedly in the latter five years period since the FPR lowered from 4.9% to 2.8% and the number of invasive procedures needed to detect one case of Down's syndrome lowered from 15 to 11.

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