National Women’s Antenatal Screening Dr Emma Parry CMFM [email protected] Clinical Director...

National Women’s National Women’s

Antenatal Screening

Dr Emma Parry CMFM

[email protected]

Clinical Director Maternal-Fetal Medicine

National Women’s Health


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 offered 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)


Criteria to be satisfied for screening

• Condition is suitable for screening• There is a suitable test• There is effective treatment for the condition• There is high quality evidence (RCTs etc) that

mortality/morbidity is reduced• Potential benefits of screening outweight any harms

caused• The Health care system is capable of supporting all

necessary parts of the screening pathway• There is consideration of social and ethical issues• There is consideration of cost-benefit issues


What is a screening programme?

A coordinated system of:• Pretest counselling• Testing with follow up• Quality assurance audits of test performance• Post test counselling• Audits of detection rates• Audits of patient satisfaction• Regular review and updating as necessary


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


Current Standard Screening Programmes

• Infection:– Rubella– Hepatitis B– Syphilis

• Malformation:– Aneuploidy– Structural– Syndromic

• Red Cell Antibodies


Variable Screening Programmes

• HIV

• Thalassaemia

• CMV

• Smear

• Swabs for infection


Areas of Difficulty• Consistency of approach to counseling

• Aneuploidy Screening– Evolving results– Soft markers on anomoly scan– Multiple pregnancy– Diabetes– Late Booker– High risk result: normal karyotype

• HIV: late booker/ in labour


Aneuploidy Screening

• Evolving results

• Soft markers on anomoly scan

• Multiple pregnancy

• Diabetes

• Late booker

• High risk result: normal karyotype


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



Aneuploidy Screening

• Evolving results

• Soft markers on anomoly scan

• Multiple pregnancy

• Diabetes

• Late booker

• High risk result: normal karyotype


Nuchal Translucency


Nuchal Translucency• Designed for low risk women (<40 years?)• USS measurement

– TA or TV– Registered user (FMF)– Ongoing audit

• 11+3 to 13+6• Bayes theory• Result is a RISK- not a diagnostic test• Trisomy 13 and 18• Detection for Trisomy 21 is 85%


Nuchal Translucency

• Nasal Bone

• Tricuspid Regurgitation

• Fronto- Maxillary facial angle

• DV

• Soft tissue thickness

• Aberrant subclavian artery

• Others?


Increased NT + Normal Karyotype

15%46.2%19.0%64.5%>6.4

30%24.2%10.1%50.5%5.5-6.4

50%18.5%3.4%33.3%4.5-5.4

70%10.0%2.7%21.1%3.5-4.4

A&WMajor

Anom

Fetal

Death

Chrom

Abn

NT (mm)


Case 1

• 44 year old grand multip– Pacific islander– All NVD

• Keen to avoid invasive testing

• NT 1.1mm = T21 risk 1:143


Case 1

• Combined with 2nd trimester screen– A-FP, Oestriol, free bHCG

• Risk T21 1:140

• Risk T18 1:8

• Risk NTD 1:2900


Case 2

• Primigravida age 29

• Unplanned pregnancy but wanted

• Epilepsy on Valproate 1000mg

• Family history Talipes


Case 2

• Wants Screening

• NT risk 1:2500– Routine 2nd trimester screening

• Risk T21 1:5400• Risk T18 1:12000• Risk NTD 1:4


Case 2

• Anomoly scan at 18/40– Difficult views– Lemon shape head and banana

cerebellum– 3D volumes = Sacral open NTD with cord

tethering


Case 3

• 37 year old primigravida

• Fertility treatment

• Low risk NT

• Very low risk combined – Risk 1 in 8000

• At anomoly scan Nasal bone short?


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


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


• 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


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



• 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



• 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


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?

National Women’s Antenatal Screening Dr Emma Parry CMFM [email protected] Clinical Director...

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