National Women’s Screening for Aneuploidy Dr Emma Parry CMFM [email protected] Clinical Director Maternal-Fetal Medicine National Women’s Health

National Women’s National Women’s

Screening for Aneuploidy

Dr Emma Parry CMFM

[email protected]

Clinical Director Maternal-Fetal Medicine

National Women’s Health


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


• What is Screening?• Why screen for aneuploidy?• Options for Screening:



– Combining tests



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)


Effect of choice of cut-off on test performancex minimises false positives

z minimises false negatives


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





– Combining tests



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





– Combining tests



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


Maternal Serum analytes

• 1st Trimester – PAPP-A– Free B-HCG

• 2nd Trimester– Alpha Fetoprotein ) )– Oestriol ) Triple Test)– Free B-HCG ) )– Inhibin-A )

Quadruple Test


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


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


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


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


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%)


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:


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%):


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





– Combining tests



2nd Trimester USS markers


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


• 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


• 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





– Combining tests



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%


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


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/

Documents

National Women’s Screening for Aneuploidy Dr Emma Parry CMFM [email protected] Clinical Director Maternal-Fetal Medicine National Women’s Health