Prenatal screening for trisomy 21: a comparative performance and cost analysis of different screening strategies

Abstract Background Prenatal screening for chromosome aneuploidies have constantly been evolving, especially with the introduction of cell-free fetal DNA (cfDNA) screening in the most recent years. This study compares the performance, costs and timing of test results of three cfDNA screening implementation strategies: contingent, reflex and primary. Methods We modelled enhanced first trimester screening (eFTS) as the first-tier test in contingent or reflex strategies. cfDNA test was performed contingent on or reflex from eFTS results. A comparison was made between cfDNA screening using sequencing technology and Rolling Circle Amplification (RCA)/imaging solution. All model assumptions were based on results from previous publications or information from the Ontario prenatal screening population. Results At an eFTS risk cut-off of ≥1/1000, contingent and reflex cfDNA screening have the same detection rate (DR) (94%) for trisomy 21. Reflex cfDNA screening using RCA/Imaging solution provided the lowest false positive rate and cost. The number of women requiring genetic counselling and diagnostic testing was significantly reduced and women received their cfDNA screening result 9 days sooner compared with the contingent model. While primary cfDNA screening improved the trisomy 21 DR by 3–5%, it was more costly and more women required diagnostic testing. Conclusion Reflex cfDNA screening is the most cost-effective prenatal screening strategy. It can improve the efficiency of prenatal aneuploidy screening by reducing the number of patient visits and providing more timely results.

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Enhanced First Trimester Screening for Trisomy 21 with Contingent Cell-Free Fetal DNA: A Comparative Performance and Cost Analysis

Journal of Obstetrics and Gynaecology Canada ◽

10.1016/j.jogc.2017.01.025 ◽

2017 ◽

Vol 39 (9) ◽

pp. 742-749 ◽

Cited By ~ 4

Author(s):

Tianhua Huang ◽

Wendy S. Meschino ◽

Mari Teitelbaum ◽

Shelley Dougan ◽

Nan Okun

Keyword(s):

Cost Analysis ◽

Trisomy 21 ◽

First Trimester ◽

First Trimester Screening ◽

Comparative Performance ◽

Fetal Dna ◽

Cell Free Fetal Dna ◽

Trimester Screening

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Current relevance of non-invasive prenatal study of cell-free fetal DNA in the mother’s blood and prospects for its application in mass screening of pregnant women in the Russian Federation

Journal of obstetrics and women s diseases ◽

10.17816/jowd56573 ◽

2021 ◽

Vol 70 (1) ◽

pp. 19-50

Author(s):

Elena A. Kalashnikova ◽

Andrey S. Glotov ◽

Elena N. Andreyeva ◽

Ilya Yu. Barkov ◽

Galina Yu. Bobrovnik ◽

...

Keyword(s):

Mass Screening ◽

Russian Federation ◽

Prenatal Screening ◽

First Trimester ◽

Screening Programs ◽

Non Invasive ◽

Fetal Dna ◽

Prenatal Diagnostic ◽

Cell Free Fetal Dna ◽

The Russian Federation

This review article offers an analysis of application of cell-free fetal DNA non-invasive prenatal screening test for chromosome abnormalities in the mothers blood in different countries. The diagnostic capacities of the method, its limitations, execution models and ethical aspects pertinent to its application are discussed. The data for the discordant results is shown and analyzed. The advantages of the genome-wide variant of cell-free fetal DNA analysis and the problems concerning its application in the mass screening are described. The main suggestion is to implement the contingent cell-free fetal DNA testing model for the common trisomies (for the chromosomes 21, 18 and 13) into the prenatal diagnostic screening programs in the Russian Federation. This novel model is based on the results of the mass combined first trimester prenatal screening in four federal subjects of the country completed by 2019 and is offered as an additional screening in the mid-level risk group (with cut-off from 1 : 100 to 1 : 500 or from 1 : 100 to 1 : 1000) defined according to the first trimester prenatal screening results. The basic requirements for the implementation of the contingent model in the Russian Federation are stated.

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Clinical and Economic Evaluation after Adopting Contingent Cell-Free DNA Screening for Fetal Trisomies in South Spain

Fetal Diagnosis and Therapy ◽

10.1159/000508306 ◽

2020 ◽

Vol 47 (10) ◽

pp. 749-756

Author(s):

José A. Sainz ◽

María R. Torres ◽

Ignacio Peral ◽

Reyes Granell ◽

Manuel Vargas ◽

...

Keyword(s):

False Positive Rate ◽

Cost Effective ◽

First Trimester ◽

Nuchal Translucency ◽

University Hospitals ◽

Combined Test ◽

Positive Rate ◽

Fetal Malformations ◽

Cfdna Screening ◽

Singleton Pregnancies

Introduction: Contingent cell-free (cf) DNA screening on the basis of the first-trimester combined test (FCT) results has emerged as a cost-effective strategy for screening of trisomy 21 (T21). Objectives: To assess performance, patients’ uptake, and cost of contingent cfDNA screening and to compare them with those of the established FCT. Methods: This is a prospective cohort study including all singleton pregnancies attending to their FCT for screening of T21 at 2 university hospitals in South Spain. When the FCT risk was ≥1:50, there were major fetal malformations, or the nuchal translucency was ≥3.5 mm, women were recommended invasive testing (IT); if the risk was between 1:50 and 1:270, women were recommended cfDNA testing; and for risks bellow 1:270, no further testing was recommended. Detection rate (DR), false-positive rate (FPR), patients’ uptake, and associated costs were evaluated. Results: We analyzed 10,541 women, including 46 T21 cases. DR of our contingent strategy was 89.1% (41/46) at 1.4% (146/10,541) FPR. Uptake of cfDNA testing was 91.2% (340/373), and overall IT rate was 2.0%. The total cost of our strategy was €1,462,895.7, similar to €1,446,525.7 had cfDNA testing not been available. Conclusions: Contingent cfDNA screening shows high DR, low IT rate, and high uptake at a similar cost than traditional screening.

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Parental Decisions about Prenatal Screening and Diagnosis among Infants with Trisomy 21 in a National Cohort with High Uptake of Combined First-Trimester Screening

Fetal Diagnosis and Therapy ◽

10.1159/000448093 ◽

2016 ◽

Vol 41 (3) ◽

pp. 209-214 ◽

Cited By ~ 3

Author(s):

Caroline Borregaard Miltoft ◽

Camilla B. Wulff ◽

Susanne Kjærgaard ◽

Charlotte K. Ekelund ◽

Ann Tabor ◽

...

Keyword(s):

Trisomy 21 ◽

Prenatal Screening ◽

First Trimester ◽

High Uptake ◽

First Trimester Screening ◽

Trimester Screening ◽

National Cohort ◽

Parental Decisions ◽

Screening And Diagnosis

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False Negative Cell-Free DNA Screening Result in a Newborn with Trisomy 13

Case Reports in Genetics ◽

10.1155/2016/7397405 ◽

2016 ◽

Vol 2016 ◽

pp. 1-5

Author(s):

Yang Cao ◽

Nicole L. Hoppman ◽

Sarah E. Kerr ◽

Christopher A. Sattler ◽

Kristi S. Borowski ◽

...

Keyword(s):

Prenatal Screening ◽

False Negative ◽

Chromosome Abnormalities ◽

Trisomy 13 ◽

Cell Free Dna ◽

Free Dna ◽

Negative Cell ◽

Cell Free Fetal Dna ◽

Cfdna Screening ◽

Screening Result

Background.Noninvasive prenatal screening (NIPS) is revolutionizing prenatal screening as a result of its increased sensitivity, specificity. NIPS analyzes cell-free fetal DNA (cffDNA) circulating in maternal plasma to detect fetal chromosome abnormalities. However, cffDNA originates from apoptotic placental trophoblast; therefore cffDNA is not always representative of the fetus. Although the published data for NIPS testing states that the current technique ensures high sensitivity and specificity for aneuploidy detection, false positives are possible due to isolated placental mosaicism, vanishing twin or cotwin demise, and maternal chromosome abnormalities or malignancy.Results.We report a case of false negative cell-free DNA (cfDNA) screening due to fetoplacental mosaicism. An infant male with negative cfDNA screening result was born with multiple congenital abnormalities. Postnatal chromosome and FISH studies on a blood specimen revealed trisomy 13 in 20/20 metaphases and 100% interphase nuclei, respectively. FISH analysis on tissues collected after delivery revealed extraembryonic mosaicism.Conclusions.Extraembryonic tissue mosaicism is likely responsible for the false negative cfDNA screening result. This case illustrates that a negative result does not rule out the possibility of a fetus affected with a trisomy, as cffDNA is derived from the placenta and therefore may not accurately represent the fetal genetic information.

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Prospective experience with integrated prenatal screening and first trimester combined screening for trisomy 21 in a large Canadian urban center

Prenatal Diagnosis ◽

10.1002/pd.2084 ◽

2008 ◽

Vol 28 (11) ◽

pp. 987-992 ◽

Cited By ~ 22

Author(s):

Nanette Okun ◽

Anne M. Summers ◽

Barry Hoffman ◽

Tianhua Huang ◽

Elizabeth Winsor ◽

...

Keyword(s):

Trisomy 21 ◽

Prenatal Screening ◽

First Trimester ◽

Urban Center

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Usefulness and reliability of cell free fetal DNA screening for main trisomies in case of atypical profile on first trimester maternal serum screening

Journal of Translational Medicine ◽

10.1186/s12967-019-02152-7 ◽

2019 ◽

Vol 17 (1) ◽

Author(s):

Julie Carrara ◽

Alexandre Vivanti ◽

Jacques C. Jani ◽

Adèle Demain ◽

Jean-Marc Costa ◽

...

Keyword(s):

Trisomy 21 ◽

Vascular Complications ◽

First Trimester ◽

Multivariate Regression Analysis ◽

Primary Objective ◽

Maternal Serum ◽

Trisomy 13 ◽

Maternal Serum Screening ◽

Cell Free Fetal Dna ◽

Atypical Values

Abstract Background Patients with atypical values of HCG and/or PAPP-A are at higher risk of chromosomal abnormality and vascular complications of pregnancy. The performance of cfDNA in this particular population has not yet been evaluated. Objectives The primary objective was to evaluate the usefulness and reliability of cfDNA in screening for trisomy 21, 18 and 13 for patients with HCG < 0.25 multiple of median (MoM), HCG > 5.0 MoM and/or PAPP-A < 0.25 MoM, PAPP-A > 2.5 MoM. The secondary objective was to evaluate the contribution of cfDNA assay for the prediction of pregnancy’s vascular complications. Method Between June 2016 and July 2017, we analysed a women cohort from all over France who had at least one first trimester serum biomarker outside of normal range, in a retrospective, observational and multicentre study. Patients were included if they had a single pregnancy, normal first trimester ultrasound examination, whatever the result of the combined first trimester screening test was. The cfDNA was analysed by massive parallel sequencing technique. The accuracy of cfDNA assay was evaluated by calculation of sensitivity and specificity, and multivariate regression analysis was used to search for predictive factors for pregnancy’s vascular complications. Results Among the 498 patients who underwent a cfDNA assay in this context, twenty-one (4.2%) were excluded because of loss to follow-up. Out of 477, test failure occurred for four patients initially, reduced to two patients (0.4%) after redrawn. CfDNA was positive for Trisomy 21 (n = 19), Trisomy 18 (n = 6) and Trisomy 13 (n = 1) and negative in 449. The sensitivity of cfDNA assay for trisomy 21 screening was 100% (19/19) (IC 95% 82.4–100) and specificity 100% (458/458) (IC 95% 99.2–100). Among the 447 patients included for prediction of vascular complications, there were four cases of pregnancy induced hypertension and 10 cases of preeclampsia, for which no predictive factor was identified. Intra Uterine growth restriction under 5th percentile (n = 44, 9.8%) was significantly associated with a low fetal fraction (OR = 0.87, IC 95% 0.79–0.96, p = 0.006). Conclusion cfDNA assay is an effective and reliable tool for women with atypical profile of first trimester serum biomarkers.

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First Trimester Biochemical Screening for Trisomy 21: The Role of Free Beta hCG, Alpha Fetoprotein and Pregnancy Associated Plasma Protein A

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456329403100504 ◽

1994 ◽

Vol 31 (5) ◽

pp. 447-454 ◽

Cited By ~ 56

Author(s):

K Spencer ◽

D A Aitken ◽

J A Crossley ◽

G McCaw ◽

E Berry ◽

...

Keyword(s):

Chorionic Gonadotropin ◽

Plasma Protein ◽

Human Chorionic Gonadotropin ◽

Trisomy 21 ◽

False Positive Rate ◽

Protein A ◽

First Trimester ◽

Serum Markers ◽

Maternal Serum ◽

Detection Rates

The potential efficacy of screening for trisomy 21 in the first trimester, using maternal serum markers α fetoprotein, free β human chorionic gonadotropin, unconjugated oestriol and pregnancy associated plasma protein A, was studied in an unselected population of women between the seventh and fourteenth week of gestation. Using a combination of α fetoprotein and free β human chorionic gonadotropin, 53% of affected pregnancies could be identified at a false positive rate of 5%. Unconjugated oestriol and pregnancy associated plasma protein A levels were lower in cases of trisomy 21, but their inclusion with other markers did not significantly improve detection rate. Monitoring the same pregnancies also in the second trimester showed that screening in the first trimester identified the same cases as in the second. We conclude that first trimester screening using free β human chorionic gonadotropin and α fetoprotein, is a viable possibility and will lead to detection rates in excess of 50%. Prospective studies are needed to confirm these observations.

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Performance characteristics of Elecsys free βhCG and PAPP-A for first trimester trisomy 21 risk assessment in gestational weeks 8+0 to 14+0

LaboratoriumsMedizin ◽

10.1515/labmed-2015-0084 ◽

2016 ◽

Vol 0 (0) ◽

Cited By ~ 1

Author(s):

Niels Tørring ◽

Carlos Aulesa ◽

Bernd Eiben ◽

Mª José Ferri ◽

Kypros H. Nicolaides ◽

...

Keyword(s):

Risk Assessment ◽

Trisomy 21 ◽

False Positive Rate ◽

Protein A ◽

First Trimester ◽

Nuchal Translucency ◽

Serological Markers ◽

Cross Sectional ◽

Positive Rate ◽

Technical Validation

AbstractScreening for fetal trisomy 21 (T21) in the first trimester includes analysis of the serological markers pregnancy-associated plasma protein A (PAPP-A) and free β-choriogonadotropin (free βhCG). With the recent launch of these assays on the cobas e and Elecsys platforms, we investigated their clinical and analytical performance.We conducted a multicenter study in 5397 pregnancies including 108 cross-sectional collected repository cases with verified fetal T21 at 8–14 weeks of gestation. A technical validation of the Roche ElecsysThe imprecision of the Elecsys free βhCG and PAPP-A assays was between 1.0% and 2.8%, and both assays showed correlation to Kryptor (free βhCG 0.981; PAPP-A 0.987), AutoDELFIA (free βhCG 0.995; PAPP-A 0.979) and IMMULITE assays (free βhCG 0.983; PAPP-A 0.983). With a cut off at 1:300 the overall sensitivity of the screening including nuchal translucency reached 94% for a 3% false positive rate.The Roche Elecsys free βhCG and PAPP-A are suitable and reliable assays for first trimester T21 risk assessment. Both assays were approved and recommended by the FMF.

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