Abstract
Purpose
To determine the false-positive rates (FPR) associated with screening for trisomy 18/13 using first-trimester combined screening (FTCS) and an ultrasound plus cfDNA-based approach (US-cfDNA), which includes a detailed ultrasound examination, a cfDNA analysis and a FTCS reflex backup test for cases with uninformative results.
Methods
This is a sub-analysis of a randomized controlled trial, which was performed between 2015 and 2016. Pregnant women with a normal first-trimester ultrasound examination at 11–13 weeks’ gestation (NT < 3.5 mm, no anomalies) were randomized into two groups: FTCS and US-cfDNA screening. The overall FPR in screening for trisomies 18/13 and 21 was compared with the FPR in screening for trisomy 21 alone. Pregnancies were considered screen positive if the risk for trisomy 21 was 1:100 and for trisomy 18 and 13, 1:20 each.
Results
The study population consisted of 688 pregnancies in each study arm. In the FCTS group, median delta NT was 0.0 mm, free beta-hCG and PAPP-A 0.96 and 1.11 MoM. In the US-cfDNA group, median delta NT was 0.0 mm. In 10 pregnancies, the cfDNA analysis was uninformative. In the FTCS and in the US-cfDNA group, the FPR in screening for trisomy 21 was 2.5% and 0%. In both groups, the overall FPR was not increased by adding screening algorithms for trisomies 18 and 13.
Conclusion
In conclusion, the addition of screening for trisomies 18 and 13 to screening for trisomy 21 does not significantly change FPR. This is true for both the FTCS and the US-cfDNA-based approach.
Similar content being viewed by others
References
Kagan KO, Sonek J, Wagner P, Hoopmann M (2017) Principles of first trimester screening in the age of non-invasive prenatal diagnosis: screening for chromosomal abnormalities. Arch Gynecol Obstet 296:645–651. https://doi.org/10.1007/s00404-017-4459-9
Kagan KO, Wright D, Baker A et al (2008) Screening for trisomy 21 by maternal age, fetal nuchal translucency thickness, free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 31:618–624. https://doi.org/10.1002/uog.5331
Kagan KO, Etchegaray A, Zhou Y et al (2009) Prospective validation of first-trimester combined screening for trisomy 21. Ultrasound Obstet Gynecol 34:14–18. https://doi.org/10.1002/uog.6412
Santorum M, Wright D, Syngelaki A et al (2017) Accuracy of first-trimester combined test in screening for trisomies 21, 18 and 13. Ultrasound Obstet Gynecol 49:714–720. https://doi.org/10.1002/uog.17283
Gil MM, Accurti V, Santacruz B et al (2017) Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol 35:156. https://doi.org/10.1002/uog.17484
Salomon LJ, Alfirevic Z, Audibert F et al (2017) ISUOG updated consensus statement on the impact of cfDNA aneuploidy testing on screening policies and prenatal ultrasound practice. Ultrasound Obstet Gynecol 49:815–816. https://doi.org/10.1002/uog.17483
Kagan KO, Sroka F, Sonek J et al (2018) First-trimester risk assessment based on ultrasound and cell-free DNA vs combined screening: a randomized controlled trial. Ultrasound Obstet Gynecol 51:437–444. https://doi.org/10.1002/uog.18905
Kagan KO, Wright D, Valencia C et al (2008) Screening for trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency, fetal heart rate, free β-hCG and pregnancy-associated plasma protein-A. Hum Reprod 23:1968–1975. https://doi.org/10.1093/humrep/den224
Wagner P, Sonek J, Hoopmann M et al (2016) First-trimester screening for trisomies 18 and 13, triploidy and Turner syndrome by detailed early anomaly scan. Ultrasound Obstet Gynecol 48:446–451. https://doi.org/10.1002/uog.15829
Wright D, Kagan KO, Molina FS et al (2008) A mixture model of nuchal translucency thickness in screening for chromosomal defects. Ultrasound Obstet Gynecol 31:376–383. https://doi.org/10.1002/uog.5299
Salomon LJ, Alfirevic Z, Bilardo CM et al (2013) ISUOG practice guidelines: performance of first-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol 41:102–113. https://doi.org/10.1002/uog.12342
von Kaisenberg C, Chaoui R, Häusler M et al (2016) Quality requirements for the early fetal ultrasound assessment at 11−13 + 6 weeks of gestation (DEGUM levels II and III). Ultraschall Med 37:297–302. https://doi.org/10.1055/s-0042-105514
Grati FR, Kagan KO (2017) Rate of no result in cell-free DNA testing and its influence on test performance metrics. Ultrasound Obstet Gynecol 50:134–137. https://doi.org/10.1002/uog.17330
Snijders RJ, Holzgreve W, Cuckle H, Nicolaides KH (1994) Maternal age-specific risks for trisomies at 9–14 weeks’ gestation. Prenat Diagn 14:543–552
Juneau K, Bogard PE, Huang S et al (2014) Microarray-based cell-free DNA analysis improves noninvasive prenatal testing. Fetal Diagn Ther 36:282–286. https://doi.org/10.1159/000367626
Sparks AB, Wang ET, Struble CA et al (2012) Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. Prenat Diagn 32:3–9. https://doi.org/10.1002/pd.2922
Sparks AB, Struble CA, Wang ET et al (2012) Noninvasive prenatal detection and selective analysis of cell-free DNA obtained from maternal blood: evaluation for trisomy 21 and trisomy 18. Am J Obstet Gynecol 206:319.e1–319.e9. https://doi.org/10.1016/j.ajog.2012.01.030
IQWiG IFQUWIG (2017) Nicht invasive Pränataldiagnostik (NIPD) zur Bestimmung des Risikos autosomaler Trisomien 13, 18 und 21 bei Risikoschwangerschaften. pp 1–118
Petersen AK, Cheung SW, Smith JL et al (2017) Positive predictive value estimates for cell-free noninvasive prenatal screening from data of a large referral genetic diagnostic laboratory. Am J Obstet Gynecol 217:691.e1–691.e6. https://doi.org/10.1016/j.ajog.2017.10.005
Funding
The study was supported by Cenata GmbH (Tübingen, Germany) and Roche Inc. (San Jose, CA, USA). The cell free DNA tests in the prospective arm of the study were carried out without additional costs.
Author information
Authors and Affiliations
Contributions
KOK: conceptualization, project development, formal analysis, funding acquisition, project administration, manuscript writing and editing; JS: manuscript writing and editing; AS: formal analysis; HA: formal analysis; PW: data collection and analysis; NP: data analysis; MH: manuscript writing and editing.
Corresponding author
Ethics declarations
Conflict of interest
All authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This is a secondary analysis of a randomized controlled study at the University of Tübingen. Approval for the prospective study was obtained from the local ethics committee (no. 572/2015BO1). The original study was registered in the International Standard Randomized Controlled Trial Number registry (ISRCTN no. 11174071). Approval for the retrospective study was also obtained from the local ethics committee (no. 531/2018BO2).
Rights and permissions
About this article
Cite this article
Kagan, K.O., Sonek, J., Sroka, A. et al. False-positive rates in screening for trisomies 18 and 13: a comparison between first-trimester combined screening and a cfDNA-based approach. Arch Gynecol Obstet 299, 431–437 (2019). https://doi.org/10.1007/s00404-018-4983-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00404-018-4983-2