1. National Women’s Screening for Aneuploidy Dr Emma Parry CMFM emmap@adhb.govt.nz Clinical Director Maternal-Fetal Medicine National Women’s Health

2. National Women’s Overview What is Screening? Why screen for aneuploidy? Options for Screening: –Maternal serum analytes –Ultrasound markers 1 st Trimester 2 nd Trimester –Combining tests Horizon scanning –New tests –New techniques

3. National Women’s What is Screening? Why screen for aneuploidy? Options for Screening: –Maternal serum analytes –Ultrasound markers 1 st Trimester 2 nd Trimester –Combining tests Horizon scanning –New tests –New techniques

4. National Women’s What is Screening? Screen: an apparatus used in the sifting of grain, coal etc. 1573 Shorter Oxford Dictionary A pathway, not a test Screening is a health service in which members of a defined population…are offerd a test to identify those who are more likely to be helped than harmed by further tests… to reduce the risk of a disease or its complications. ( National Health Committee 2003)

5. National Women’s Effect of choice of cut-off on test performance x minimises false positives z minimises false negatives

6. National Women’s Screening Tests Sensitivity a/(a+c) test Specificity d/(b+d) test +ve pred valuea/(a+b) cond -ve pred valued/(c+d) cond Prevalence condition in population (a+c)/(a+b+c+d) LR+ = sens/(1- spec) LR- = (1-sens)/spec ab cd test condition present absent +ve -ve

7. National Women’s What is Screening? Why screen for aneuploidy? Options for Screening: –Maternal serum analytes –Ultrasound markers 1 st Trimester 2 nd Trimester –Combining tests Horizon scanning –New tests –New techniques

8. National Women’s Why screen for aneuploidy? Provide information about risk to patients Describe choices for invasive testing Ensure this information is accurate Reassure the majority of women at an early stage Include most affected pregnancies in a ‘high risk’ group

9. National Women’s What is Screening? Why screen for aneuploidy? Options for Screening: –Maternal serum analytes –Ultrasound markers 1 st Trimester 2 nd Trimester –Combining tests Horizon scanning –New tests –New techniques

10. National Women’s ONTD Screening Total hCG Total hCG free  hCG Second trimester: AFP Only Second trimester: AFP Only 1st Trimester free  hCG 1st Trimester free  hCG 1st Trimester PAPP-A 1st Trimester PAPP-A 1st Trimester Nuchal Translucency 1st Trimester Nuchal Translucency ADAM12 / PP13 Advances in screening for trisomy 21 NB / TR / DV Integrated Combined Sequential Mat age

11. National Women’s Maternal Serum analytes 1 st Trimester –PAPP-A –Free B-HCG 2 nd Trimester –Alpha Fetoprotein)) –Oestriol) Triple Test) –Free B-HCG)) –Inhibin-A) Quadruple Test

12. National Women’s 0 2 4 6 8 10 12 14 16 18 20 -3.5-2.5-1.5-0.50.51.52.53.5 Free ßhCG (SD) % Trisomy 21 Normal 20 0 2 4 6 8 10 12 14 16 18 -3.5-2.5-1.5-0.50.51.52.5 PAPP-A (SD) % Normal Trisomy 21 First trimester screening for trisomy 21 Detection rates at 12 weeks are similar to those at 16 weeks Detection rates at 12 weeks are similar to those at 16 weeks Biochemical changes are independent of fetal NT thickness Biochemical changes are independent of fetal NT thickness NT, free ß-hCG and PAPP-A identifies 90% of cases for FPR of 5% NT, free ß-hCG and PAPP-A identifies 90% of cases for FPR of 5% Maternal serum free ß-hCG & PAPP-A

13. National Women’s 0 2 4 6 8 10 12 14 16 18 20 -3.5-2.5-1.5-0.50.51.52.53.5 Free ß-hCG & Inhibin A % 20 0 2 4 6 8 10 12 14 16 18 -3.5-2.5-1.5-0.50.51.52.5 AFP & uE3 % Tr 21 FPR 5% 59% 63%63%67%72% MA and AFP & hCG MA and AFP & hCG & uE3 MA and AFP & ß-hCG MA and AFP & ß-hCG & uE3 MA and AFP & ß-hCG & uE3 & I A Cuckle 2001 DR 65% Second trimester screening for trisomy 21 Detection rates

14. National Women’s So what does it all mean? Combined 1 st Trimester screening –NT + 1 st trimester analytes Integrated Screening –NT + 1 st & 2 nd trimester analytes Sequential Screening –NT + 1 st trimester analytes High risk invasive testing Low risk 2 nd trimester analytes Contingent Screening –NT + 1 st trimester analytes High risk invasive testing Moderate risk 2 nd trimester analytes Very low risk (eg <1:1500) no further testing

15. National Women’s Which approach is best? Acceptable false positive rate and unnecessary intervention Acceptable false negative and risk of failure to detect aneuploidy Patient acceptability –Early results –Later results, increased accuracy –Concept of evolving risk Cost & availability non-invasive testing Late bookers Invasive testing issues –Availability –Complications

16. National Women’s Combined first trimester screening AuthorGest (wks)NDetection rate Krantz et al 200010-13 +6 5,80930/33 (91%) Bindra et al 200211-13 +6 14,38374/82 (90%) Spencer et al 2000; 200310-13 +6 11,10523/25 (92%) Schuchter et al 200210-13 +6 4,80212/14 (86%) Wapner et al. 200310-13 +6 8,51448/61 (79%) Perni et al. 200611-13 +6 4,88320/22 (91%) O’Leary et al. 200611-13 +6 22,28050/60 (83%) Total71776257/297 (87%)

17. National Women’s FASTER Trial: Trisomy 21 n=86, Normal n=32,269 Integrated: 11-13w NT & PAPP-A 15-18w AFP, hCG, E 3, I A 4.9% 88% Sequential: 11-13w NT & PAPP-A, ßhCG Risk >1 in 30 positive(1.2%) Risk <1 in 30: 15-18w AFP, hCG, E 3, I A 5.1% 92% Cuckle, Malone, Write et al 2008 Contingent: 11-13w NT & PAPP-A, ß-hCG Risk >1 in 30 positive (1.2%) Risk 1/30 to 1/1500 (23%): 15-18w AFP, hCG, E 3, I A 4.5% 91% FPR DR

18. National Women’s 8 10 12 14 16 18 20 22 0 2 4 6 8 10 Gestation (wks) Deaths / 100,000 abortions 0.5 4 Bartlett et al 2004 Induced abortion-related maternal mortality: USA 1988-1997

19. National Women’s What is Screening? Why screen for aneuploidy? Options for Screening: –Maternal serum analytes –Ultrasound markers 1 st Trimester 2 nd Trimester –Combining tests Horizon scanning –New tests –New techniques

20. National Women’s 2 nd Trimester USS markers

21. National Women’s 2 nd Trimester USS markers Concept of prior risk Can include –Maternal age –NT +/- NB, TR –Serum analytes: 1 st +/or 2 nd trimester Bayseian technique to allow risk adjustment ‘USS soft markers lead to a small increase in detection malformations and large increase in false positives’ Boyd et al, Lancet 1998

22. National Women’s Absent NB X83 Hypoplastic NB (16/40<3.0mm)* (20/40<4.5mm)* Increased NFX17 Echogenic bowelX6 Short femurX2.7 Short humerusX7.5 PyelectasisX1 Bethune 2007 Aus Radiol 51;218-225

23. National Women’s Echogenic intracardiac focus –Micro-calcifications in papillary muscle –No effect per se –Small association Trisomy 21 in high risk –No increase in unselected populations –LR X 1 CP cysts –Associated with Trisomy 18 –Will nearly always have another feature eg clenched hands Bethune 2007 Aus Radiol 51;324-329

24. National Women’s What is Screening? Why screen for aneuploidy? Options for Screening: –Maternal serum analytes –Ultrasound markers 1 st Trimester 2 nd Trimester –Combining tests Horizon scanning –New tests –New techniques

25. National Women’s New Tests ADAM 12 PAPP-A –Earlier gestation increases accuracy: 8/40 –Repeated testing New markers?

26. National Women’s Laigaard et al. 2003 / 2006 An extra serum marker: ADAM12 Performance <11 weeks: TestSensFPR A1278%1.5% A12 / BhCG/ PaPPA85%1.5% Triple biochem / NT92%0.8%

27. National Women’s New Techniques Bloodspots  Simplified blood collection and transport  Eliminates broken transport tubes  Reduced biohazard  Eliminates need for centrifugation  Can be finger prick or venous sample  Can be self-sampling or by a phlebotomist  Suitable for large scale automation and regional screening modalities

28. National Women’s OSCAR in Calgary* One Stop Clinic for Assessment of Risk Southern Alberta Centre for MFM (NT clinic + Astraia) + (DELFIAXpress + Lifecycle) = OSCAR Woman arrives Pre-test counselling* Blood sample Ultrasound Examination Risk Assessment Post-test counselling Woman departs Free b HCG PAPP-A *1-1 counselling, video, pamphlets U/S data Invasive testing usually not same day

29. National Women’s Screening for Aneuploidy Good reasoning Complex haphazard introduction of tests Tests initially hailed ‘100% accurate’ Have we opened Pandora’s box? http://elena.aut.ac.nz/homepages/staf f/Dave-Parry/docs.html http://elena.aut.ac.nz/homepages/staf f/Dave-Parry/docs.html http://mfmnewzealand.blogspot.com/