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Prenatal Screening for Trisomy 21: Recent Advances and Guidelines Jacob Canick, PhD Alpert Medical School of Brown University Women & Infants Hospital Providence, RI, USA Department of Pathology Montefiore Medical Center Bronx, NY March 17, 2011. Women & Infants’. BROWN.

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  1. Prenatal Screening for Trisomy 21: Recent Advances and Guidelines Jacob Canick, PhD Alpert Medical School of Brown University Women & Infants Hospital Providence, RI, USA Department of Pathology Montefiore Medical Center Bronx, NY March 17, 2011 Women & Infants’ BROWN

  2. Disclosure Information Grant & Research Support: • Beckman Coulter, Inc., Brea, CA • Beckman Coulter Foundation, Brea, CA • Sequenom, Inc., San Diego, CA Other: • Patent Holder – uE3 in prenatal screening

  3. Prenatal Screening for Trisomy 21: Recent Advances and Guidelines • Brief history of prenatal screening • How is screening performance measured? • Performance of second trimester, first trimester, integrated, and sequential tests for Down syndrome • Guidelines: standard of practice in EUROCAT countries and the United States • Trisomy 18 and 13 • Laboratory issues in prenatal screening

  4. Brief history of prenatal screening

  5. Prenatal Screening History Begins with Prenatal Screening for Open Neural Tube Defects using MSAFP 4 per 1000 births Spina bifida Anencephaly 1970s AFP in maternal serum elevated in NTDs 1970s Maternal Serum AFP screening 1980s acceptance in U.S. (ACOG liability alert) 1980s primary prevention with folic acid 2000s move to ultrasound screening? The birth prevalence of spina bifida and anencephaly in England and Wales between 1964 and 1975. (N Wald)

  6. Prenatal Screening History Begins with Prenatal Screening for Open Neural Tube Defects using MSAFP 0.3 per 1000 births Effect of primary prevention (folic acid) and prenatal screening(MSAFP) The birth prevalence of spina bifida and anencephaly in England and Wales between 1964 and 1993. (N Wald)

  7. 1930 Down syndrome – maternal age association 1940 1950 Down syndrome caused by chromosome trisomy (2009, the 50th Anniversary of discovery by LeJeune) 1960 1970 Prenatal Screening for Aneuploidies: History Screening using maternal age, offer of amnio 1980 2nd trim AFP (with Mat Age)* 1990 2nd trim Multiple markers (Double, Triple, Quad) 1st trim nuchal translucency (NT) 1st trim NT + PAPP-A + free bhCG 2000 Integrated 1st and 2nd trim Sequential 1st and 2nd trim 2011 Fetal nucleic acids in maternal plasma?

  8. Maternal Serum Markers in the 2nd Trimester:Major improvement in screening for Down syndrome • Background • 1980s Maternal age as a reason for amniocentesis. • 1980sMaternal serum AFP already in use in screening for open NTDs. • 1984 Maternal serum AFP is low in Down syndrome pregnancy. Irwin Merkatz, MD Albert Einstein Col. Med.

  9. How is screening performance measured?

  10. Screening Performance: The challenge in screening is to have a test that has a high detection rate and low false positive rate. Detection Rate percentage of affecteds called (sensitivity) screen positive by the test The higher the better! False Positive Rate percentage of unaffecteds called (1 – specificity) screen positive by the test The lower the better!

  11. Performance of second trimester, first trimester, integrated, and sequential tests for Down syndrome

  12. Screening in the Early 2nd Trimester (15-20 weeks)with Multiple Serum Markers 0 13 26 40 weeks • Advantages: • Simplest screening method (all serum at one time) • Includes screening for open NTDs using MSAFP • Will include a larger proportion of pregnant women • Follow-up diagnostic test is amniocentesis

  13. 10 1.91 2.00 MoM 1 0.74 0.61 .1 AFP uE3 inhA hCG 2nd Trimester Serum Markers in Down Syndrome Pregnancies Data from FASTER

  14. Prenatal Screening for Down Syndrome in the Early 2nd Trimester (15 -20 weeks) SURUSS FASTER at 5% false positive rate 100 90 81% 79% 80 74% 72% 70 66% 60 Detection Rate (%) 50 40 30% 30 20 59% 69% 79% 10 0 MA + double triple quad ---2nd trimester-----

  15. Screening in the Late 1st Trimester (11-13 weeks) 0 13 26 40 weeks • Advantages: • Patient privacy • Earlier diagnosis (if CVS is available) • Greater availability of pregnancy termination • Earlier, safer pregnancy termination

  16. 10 2.29 1.99 MoM 1 0.50 .1 NT fb-hCG PAPP-A F Malone, with permission • First Trimester • Combined Test: • NT ultrasound • serum PAPP-A • serum b-hCG Data from FASTER

  17. Prenatal Screening for Down Syndrome in the Late 1st Trimester (11-13 weeks) at 5% false positive rate 100 90 85% 79% SURUSS FASTER BUN 80 69% 68% 62% 70 60 Detection Rate (%) 50 40 30 64% 85% 20 30% 69% 79% 10 0 MA + triple quad NT combined 2nd trimester 1st trimester

  18. The Integrated Test:Two Stages to Reach a Single Risk Assessment Wald NJ et al. N Eng J Med 1999 • Combination of the best markers measured at different times in pregnancy into a single test result. • This will be more effective than current tests performed at any one time. 0 13 26 40 weeks PAPP-A + quad markers = SERUM INTEGRATED NT + PAPP-A + quad markers = FULL INTEGRATED Integrate results into a single risk

  19. Performance of the Integrated Test SURUSS FASTER at 5% false positive rate 94% 95% 93% 100 85% 85% 89% 86% 90 85% 79% 80 69% 70 60 Detection Rate (%) 50 40 30% 30 20 10 0 MA + triple quad combined serum full 2nd trimester 1st trimester -integrated-

  20. Performance of the Integrated Test SURUSS FASTER at 1% false positive rate 100 85% 87% 86% 90 72% 80 73% 70% 66% 66% 60% 70 50% 60 Detection Rate (%) 50 40 30 12% 20 10 0 MA + triple quad combined serum full 2nd trimester 1st trimester -integrated- 85% DR at 1%

  21. Relative Screening Performance of 1st Trimester Combined and Integrated Tests

  22. Is there a way to have both: earlier screening and diagnosis – as in the 1st trimester test and much lower screen positive rate – as in the Integrated Test YES Sequential protocols

  23. 100 Full Integrated 90 Sequential protocols Detection rate (%) First Trimester Combined 80 70 2 3 4 5 False positive rate (%) Sequential Screening: Towards 1st trimester combined or towards integrated, depending on the 1st trimester risk cut-off

  24. Example of Sequential Screening Palomaki et al. Obstet Gynecol 2006;107:367-75. DRFPR Step 1. 1st trimester markers measured on all women at 10-13 wk. Risk cut-off set at ≥ 1:6371.8% 1.5% Step 2. Screen negatives (98.5% of population) have quad markers measured at 15-18 wk. Risk cut-off set at ≥ 1:6512.5% 0.5% Overall 84.3% 2.0% Assumes 1:600 prevalence

  25. Comparing Sequential Screening to 1st Trimester Combined Test and Integrated Test Palomaki et al. Obstet Gynecol 2006;107:367-75. FPR to get 84.3% DR 6.0% 2.0% 1.2%

  26. Stage 1: • 1st trimester markers • PAPP-A and NT • 1:25 risk cut-off • 59% DR, 0.9% FPR • Stage 2: • Quad markers • Full Integrated Risk • 1:110 risk cut-off • 31% DR, 1.6% FPR SequentialIntegratedScreening at Women & Infants (Expected Performance) Sequential Integrated Test: 90% DR, 2.5% FPR Compare to Integrated Test: 90% DR, 2.0% FPR Compare to 1st TrimesterTest: 90% DR, 8.0% FPR

  27. Prenatal Screening Guidelines: Practice Standards in the United States

  28. American College of Obstetricians and Gynecologists (ACOG) January 2007

  29. ACOG 2007 “… all women should be offered aneuploidy screening before 20 weeks of gestation, regardless of maternal age.” “… patients seen early in pregnancy should be offered aneuploidy screening that combines first- and second-trimester testing (integrated or sequential).” “The screening strategy chosen will depend on availability of CVS and of personnel trained in NT measurement …” ACOG Practice Bulletin, No. 77, January 2007

  30. ACOG 2007 “When CVS is not available, … offer integrated screening to patients who present in the first trimester … to take advantage of the improved detection rate and low false-positive rate.” “If NT measurement is not available or cannot be obtained …, offer serum integrated screening to patients who present early and second-trimester screening to those who present later.” ACOG Practice Bulletin, No. 77, January 2007

  31. Trisomy 18 (Edwards Syndrome) and Trisomy 13 (Patau Syndrome)

  32. Trisomy 18: Marker Levels GE Palomaki 2011, analysis of published literature PAPP-A 0.10

  33. Trisomy 18: Screening Performance GE Palomaki 2011, unpublished

  34. Trisomy 13 • 2nd trimester markers are not informative. • 1st trimester markers are informative. • Their pattern is similar to that found in trisomy 18. • But, published data on trisomy 13 marker levels are biased and too small to estimate their levels with accuracy. • It is reasonable to assume that the majority of trisomy 13 cases will be identified as part of current trisomy 18 screening protocols that include 1st trimester markers.

  35. Laboratory Issues in Prenatal Screening • Serum marker assays • Free b-hCG or total b-hCG in the 1st trimester • Screening marker quality assurance • Nuchal Translucency ultrasound and the laboratory

  36. Prenatal Screening: Serum Assays

  37. free b subunit or hCG itself in the 1st trimester? free b hCG hCG Palomaki GE et al. Adv Clin Chem 2007;43:177-210.

  38. + PAPP-A + PAPP-A + free b + PAPP-A + hCG First Trimester Screening Performance(NT + serum markers): SURUSS 100 95 90 85 DR @ 5% FPR 80 75 70 65 60 9 10 11 12 13 14 Gest age (weeks) Wald et al., J Med Screen 2003;10:56-104.

  39. + PAPP-A + PAPP-A + free b + PAPP-A + hCG First Trimester Screening Performance(NT + serum markers): FASTER 100 95 90 85 DR @ 5% FPR 80 75 70 65 60 10 11 12 13 14 Gest age (weeks) Canick et al., Obstet Gynecol 2006;108:1192-9.

  40. + PAPP-A + PAPP-A + free b + PAPP-A + hCG First Trimester Screening Performance(NT + serum markers): Evans meta-analysis 100 95 90 85 DR @ 5% FPR 80 75 70 65 60 9 10 11 12 Gest age (weeks) Evans et al., Am J Obstet Gynecol, March 2007

  41. free b subunit or hCG itself in the 1st trimester? • Univariately, free-b is a better 1st trimester marker than hCG itself. • Multivariately, between 11 and 13 gestational weeks, it makes little difference whether free-b or hCG is used. • Because of patent issues in the U.S., most labs currently use hCG in 1st trimester screening.

  42. Prenatal Screening Quality Assurance Applying Serum Marker Quality Assurance Measures to Nuchal Translucency (NT)

  43. Prenatal Screening Markers Quality monitoring Marker parameters that are monitored: Rate of change with may go up or down at a constant increasing gestation rate Median calculated MoM values should be stable at 1.0 SD of the distribution calculated SD of the log MoM values expected to remain steady

  44. log-linear increase slope = +15% per week (median MoM) unaffected distribution (x and SD) MS AFP (MoM) Examples of Marker QA Parameters

  45. Nuchal Translucency (NT) Measurement F Malone, with permission http://www.fetalmedicine.com “increased nuchal translucency” “normal nuchal translucency”

  46. 1st Trimester Nuchal Translucency (NT) Quality monitoring NT parameters that are monitored: Rate of increase with CRL log-linear over 10,3 - 13,6 weeks should go up by ~ 20% per week Median calculated MoM values should be stable at 1.0 MoM SD of the distribution calculated SD of the log MoM values expected to be about 0.1

  47. log-linear increase slope = +15% per week log-linear increase slope = +20% per week Maternal Serum AFP Increases with Increasing Gestation Nuchal Translucency Increases with Increasing Gestation Schuchter et al, Prenat Diagn 1998

  48. NT in Down Syndrome UK SURUSS Trial: NT measurement (mm) in 75 pregnancies with Down syndrome according to CRL Wald NJ et al, Health Technology Assessment 2003; Vol. 7: No. 11

  49. unaffected affected unaffected affected unaffected affected Overlapping Distributions: First Trimester Markers NT PAPP-A fb-hCG

  50. AFP MS AFP (MoM) NT NT (MoM) SD of log MoM = 0.15 The Distribution of AFP and NT MoM in Unaffected Pregnancies SD of log MoM = 0.10

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