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National Women’s National Women’s
Screening for Aneuploidy
Dr Emma Parry CMFM
Clinical Director Maternal-Fetal Medicine
National Women’s Health
National Women’s National Women’s
Overview• What is Screening?• Why screen for aneuploidy?• Options for Screening:
– Maternal serum analytes– Ultrasound markers
• 1st Trimester• 2nd Trimester
– Combining tests
• Horizon scanning– New tests– New techniques
National Women’s National Women’s
• What is Screening?• Why screen for aneuploidy?• Options for Screening:
– Maternal serum analytes– Ultrasound markers
• 1st Trimester• 2nd Trimester
– Combining tests
• Horizon scanning– New tests– New techniques
National Women’s 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)
National Women’s National Women’s
Effect of choice of cut-off on test performancex minimises false positives
z minimises false negatives
National Women’s National Women’s
Screening Tests
• Sensitivity a/(a+c) test• Specificity d/(b+d) test• +ve pred value a/(a+b) cond
• -ve pred value d/(c+d) cond
• Prevalence condition in population
(a+c)/(a+b+c+d)• LR+ = sens/(1- spec)• LR- = (1-sens)/spec
a b
c d
test
condition
present absent
+ve
-ve
National Women’s National Women’s
• What is Screening?• Why screen for aneuploidy?• Options for Screening:
– Maternal serum analytes– Ultrasound markers
• 1st Trimester• 2nd Trimester
– Combining tests
• Horizon scanning– New tests– New techniques
National Women’s 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
National Women’s National Women’s
• What is Screening?• Why screen for aneuploidy?• Options for Screening:
– Maternal serum analytes– Ultrasound markers
• 1st Trimester• 2nd Trimester
– Combining tests
• Horizon scanning– New tests– New techniques
National Women’s National Women’s
ONTD Screening
ONTD Screening
TotalhCGTotalhCG
free hCGfree hCG
Second trimester: AFP Only
Second trimester: AFP Only
1st Trimesterfree hCG
1st Trimesterfree hCG
1st TrimesterPAPP-A
1st TrimesterPAPP-A
1st TrimesterNuchal Translucency1st TrimesterNuchal Translucency
ADAM12 / PP13ADAM12 / PP13
Advances in screening for trisomy 21
NB / TR / DVNB / TR / DV
IntegratedIntegrated
CombinedCombined
SequentialSequential
Mat ageMat age
National Women’s National Women’s
Maternal Serum analytes
• 1st Trimester – PAPP-A– Free B-HCG
• 2nd Trimester– Alpha Fetoprotein ) )– Oestriol ) Triple Test)– Free B-HCG ) )– Inhibin-A )
Quadruple Test
National Women’s National Women’s
0
2
4
6
8
10
12
14
16
18
20
-3.5 -2.5 -1.5 -0.5 0.5 1.5 2.5 3.5
Free ßhCG (SD)
%Trisomy
21Normal20
0
2
4
6
8
10
12
14
16
18
-3.5 -2.5 -1.5 -0.5 0.5 1.5 2.5
PAPP-A (SD)
% NormalTrisomy
21
First trimester screening for trisomy 21First trimester screening for trisomy 21
• Detection rates at 12 weeks are similar to those at 16 weeksDetection 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
National Women’s National Women’s
00
22
44
66
88
1010
1212
1414
1616
1818
2020
-3.5-3.5 -2.5-2.5 -1.5-1.5 -0.5-0.5 0.50.5 1.51.5 2.52.5 3.53.5
Free ß-hCG & Inhibin AFree ß-hCG & Inhibin A
%%2020
00
22
44
66
88
1010
1212
1414
1616
1818
-3.5-3.5 -2.5-2.5 -1.5-1.5 -0.5-0.5 0.50.5 1.51.5 2.52.5
AFP & uE3AFP & uE3
%% Tr 21Tr 21Tr 21Tr 21
FPR FPR 55%%
5959%%
63%63%
63%63%
67%67%
72%72%
MA and AFP & hCGMA and AFP & hCG
MA and AFP & hCG & uE3MA and AFP & hCG & uE3
MA and AFP & MA and AFP & ß-hCGß-hCG
MA and AFP & MA and AFP & ß-hCGß-hCG & uE3 & uE3
MA and AFP & MA and AFP & ß-hCGß-hCG & uE3 & I & uE3 & IAA
Cuckle 2001Cuckle 2001
DR 65%
Second trimester screening for trisomy 21Second trimester screening for trisomy 21
Detection rates
National Women’s National Women’s
So what does it all mean?• Combined 1st Trimester screening
– NT + 1st trimester analytes
• Integrated Screening– NT + 1st & 2nd trimester analytes
• Sequential Screening– NT + 1st trimester analytes
• High risk invasive testing• Low risk 2nd trimester analytes
• Contingent Screening– NT + 1st trimester analytes
• High risk invasive testing• Moderate risk 2nd trimester analytes• Very low risk (eg <1:1500) no further testing
National Women’s 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
National Women’s National Women’s
Combined first trimester screeningCombined first trimester screening
Author Gest (wks) N Detection rate
Krantz et al 2000 10-13+6 5,809 30/33 (91%)
Bindra et al 2002 11-13+6 14,383 74/82 (90%)
Spencer et al 2000; 2003 10-13+6 11,105 23/25 (92%)
Schuchter et al 2002 10-13+6 4,802 12/14 (86%)
Wapner et al. 2003 10-13+6 8,514 48/61 (79%)
Perni et al. 2006 11-13+6 4,883 20/22 (91%)
O’Leary et al. 2006 11-13+6 22,280 50/60 (83%)
Total 71776 257/297 (87%)
National Women’s National Women’s
FASTER Trial: Trisomy 21 n=86, Normal n=32,269
Integrated: 11-13w NT & PAPP-A
15-18w AFP, hCG, E3, IA
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, E3, IA
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, E3, IA
4.5% 91%
FPR DR
National Women’s National Women’s8 10 12 14 16 18 20 22
0
2
4
6
8
10
Gestation (wks)
Dea
ths
/ 100
,000
abo
rtio
ns
0.5
4
Bartlett et al 2004
Induced abortion-related maternal mortality: USA 1988-1997
National Women’s National Women’s
• What is Screening?• Why screen for aneuploidy?• Options for Screening:
– Maternal serum analytes– Ultrasound markers
• 1st Trimester• 2nd Trimester
– Combining tests
• Horizon scanning– New tests– New techniques
National Women’s National Women’s
2nd Trimester USS markers
National Women’s National Women’s
2nd Trimester USS markers• Concept of prior risk• Can include
– Maternal age– NT +/- NB, TR– Serum analytes: 1st +/or 2nd 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
National Women’s National Women’s
• Absent NB X83
• Hypoplastic NB (16/40<3.0mm)*
(20/40<4.5mm)*
• Increased NF X17
• Echogenic bowel X6
• Short femur X2.7
• Short humerus X7.5
• Pyelectasis X1
Bethune 2007 Aus Radiol 51;218-225
National Women’s 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
National Women’s National Women’s
• What is Screening?• Why screen for aneuploidy?• Options for Screening:
– Maternal serum analytes– Ultrasound markers
• 1st Trimester• 2nd Trimester
– Combining tests
• Horizon scanning– New tests– New techniques
National Women’s National Women’s
New Tests
• ADAM 12
• PAPP-A– Earlier gestation increases accuracy: 8/40– Repeated testing
• New markers?
National Women’s National Women’sLaigaard et al. 2003 / 2006
An extra serum marker: ADAM12
Performance <11 weeks:
Test Sens FPR
A12 78% 1.5%
A12 / BhCG/ PaPPA 85% 1.5%
Triple biochem / NT 92% 0.8%
National Women’s 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
National Women’s 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/staff/Dave-Parry/docs.html
• http://mfmnewzealand.blogspot.com/