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Prenatal screening: state of the art in 2015

Explore the state-of-the-art prenatal screening options in 2015, from sequential combined methods to non-invasive prenatal testing (NIPT) using fetal DNA analysis. Learn about the performance, advantages, and challenges of different screening techniques.

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Prenatal screening: state of the art in 2015

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  1. Prenatal screening: state of the art in 2015 François Audibert

  2. Conflicts of interest • None!

  3. Objectives • To review the advantages and disadvantages of different prenatal screening options • Describe the objectives and results of first trimester ultrasound • Discuss the evolution of prenatal screening programs with the availability fetal DNA analysis

  4. 40 years of prenatal screening Sequential Combined Integrated Contingent 1970 2010 1980 2020 ? 1990 2000

  5. Performance

  6. SOGC guidelines – 2007 - 2011 1. All pregnant women in Canada, regardless of age, should be offered, through an informed counselling process, the option of a prenatal screening test for the most common clinically significant fetal aneuploidies… (I-A) 2. Maternal age alone is a poor minimum standard for prenatal screening for aneuploidy, and it should not be used a basis for recommending invasive testing when non-invasive prenatal screening for aneuploidy is available… (II-2A)

  7. Nuchal translucency “the skin is deficient in elasticity. . . . . . too large for the body” Langdon Down Clinical Lecture Reports, London Hospital 1866;3:259

  8. Nuchal translucency • Most efficient ultrasound screening tool • 11-13 weeks • Very dependent on technique and equipment • Should be performed with adequate quality control • Should be combined to serum screening • Continuous audit of results should be in place

  9. NT criterias • Sagittal view • Neutral position • Adequate zoom • Largest area • Calipers placement • Thin and clear membrane Standardized training International guidelines Free training and licensing www.fetalmedicine.com

  10. Combined screening: NT + serum

  11. Home Ultrasound Free βhCG PAPP-A 30 minutes CVS « One Stop Clinic for Assessment of Risk» <1/300 >1/300 The world according to Kypros Nicolaides

  12. OSCAR clinic : results • 1998-2002 • N=32,372 women • High risk (≥ 1/300) = 5.8% • 117 T21 / 127 identified by the test • Sensitivity = 92% Spencer and Nicolaides, Ultrasound Obstet Gynecol 2003

  13. 2nd trimester serum markers • 15-20 weeks • AFP • Estriol • hCG • Inhibine A

  14. «Integrated screening » • Wald et al., N Engl J Med 1999 • Estimation of FPR and DR, by various strategies (modelisation) • Triple or quadruple serum screening • NT + MSS 1st trimester (Combined Test) • NT + MSS 1st and 2ndtrimester (Integrated Test)

  15. FASTER study : results Malone, D’Alton et al. N Engl J Med 2005

  16. COMBINED Earlier diagnosis One single blood sample Organisation more simple INTEGRATED Two-step process Lower FPR Cost effectiveness? Same sensitivity More complex for women and clinicians Combined or integrated screening?

  17. <1/1000 STOP Integrated (Quad test) 1/100 to 1/1000 Karyotype (CVS or amnio) >1/100 « Contingent screening »The best of two worlds? Combined test (NT + hCG + PAPP-A)

  18. Conclusion (« conventional » screening) • Maternal age alone has a false positive rate of 10-15% (detection rate 30-50%) • Quality assurance is more important than the type of screening • Ultrasound (dating at least, but ideally NT) is of paramount importance for a good screening

  19. Non Invasive Prenatal Testing (NIPT)Cell-free Fetal DNA

  20. Introduction • Fetal cells circulate in maternal blood • Cell-free fetal DNA circulates in maternal blood Separate maternal / fetal cells Sort with various techniques Few cells: need for enrichment More DNA than free cells (20-100x) Represents ~10% of total circulating free DNA

  21. Free fetal DNA • Placental origin • Increase during pregnancy : 3-10 % of total plasmatic DNA • Cleared from maternal circulation in <24 h after delivery(1/2 life=15 min)

  22. Sparks, 2012 «  Blinded set » n=167 Harmony Test (Ariosa) High risk women All cases of T21 and T18 had a risk >99% T18 T21

  23. Test « MPSS » (Verinata/Illumina), N=1912 • Prenatal screening, unselected population • PPV45%, NPV100% • 5 T21 • 2 T18

  24. Large-scale study in unselected population NEJM, April 2015 N=15,841 pregnancies Routine screening T21 Harmony Test Sens= 100% (38 of 38) FPR= 0.06% PPV= 80.9%

  25. $$$...

  26. Contingent approach? • 74561 women • 597 anomalies • 97% ofT21 • 98% of T18, 13 • 0.8% positive test • Misses some other anomalies Syngelaki Fetal Diag Ther 2014

  27. First line test? • 0.9% False positive • 98.6% T21 • 95.7% T18, 13 • No other anomaly detected (Turner, 46XXY, triploïdies…) • High cost

  28. USA, 2008-2013

  29. NIPT: not a karyotype ! R. Wapner

  30. NIPT vs. CGH ?

  31. Some limitations • Depending on the methodologyused, reasons for discordancybetweencfDNAresults and fetalkaryotypecaninclude: • truefetalmosaicism • confinedplacentalmosaicism • maternalkaryotypeabnormality • insufficientcounting due to lowfetal fraction • vanishingtwin

  32. Guidelines / Genetics committeeSOGC Feb 2013 1. Non-invasive prenatal testing using massive parallel sequencing of cell-free fetal DNA to test for trisomies 21, 18, and 13 should be an option available to women at increased risk in lieu of amniocentesis. Pretest counselling of these women should include a discussion of the limitations of non-invasive prenatal testing. (II-2A)

  33. GuidelinesSOGC Feb 2013 2. No irrevocable obstetrical decision should be made in pregnancies with a positive non-invasive prenatal testing result without confirmatory invasive diagnostic testing. (II-2A)

  34. GuidelinesSOGC Feb 2013 3. Although testing of cell-free fetal DNA in maternal plasma appears very promising as a screening test for Down syndrome and other trisomies, studies in average-risk pregnancies and a significant reduction in the cost of the technology are needed before this can replace the current maternal screening approach using biochemical serum markers with or without fetal nuchal translucency ultrasound. (III-A)

  35. The PEGASUS study…

  36. Take home messages • NIPT is no longer a « research » tool • NIPT is performed by sequencing cell-free fetal DNA • Validated applications: • Trisomies 13, 18 and 21 in high-risk women • Second-line test after positive screening • More research needed for screening in low risk women / integration with existing screening strategies

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