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

2. What is Screening? A pathway, not a test
Screen: an apparatus used in the sifting of grain, coal etc 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)

3. 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

4. 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

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

6. Screening Tests Sensitivity a/(a+c) test Specificity d/(b+d) test
condition
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
present
absent a b c d
+ve
test
-ve

7. Current Standard Screening Programmes
Infection:
Rubella
Hepatitis B
Syphilis
Malformation:
Aneuploidy
Structural
Syndromic
Red Cell Antibodies

8. Variable Screening Programmes
HIV
Thalassaemia
CMV
Smear
Swabs for infection

9. 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

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

11. 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

12. Aneuploidy Screening Evolving results Soft markers on anomoly scan
Multiple pregnancy
Diabetes
Late booker
High risk result: normal karyotype

13. 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

14. Hypoplastic NB (16/40<3.0mm)* (20/40<4.5mm)* Increased NF X17
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
Increased NF if previous NT less likely to indicate aneuploidy. Need to consider early hydrops or cystic hygroma
Bethune 2007 Aus Radiol 51;

15. 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;

16. Aneuploidy Screening Evolving results Soft markers on anomoly scan
Multiple pregnancy
Diabetes
Late booker
High risk result: normal karyotype

17. Aneuploidy Screening Evolving results Soft markers on anomoly scan
Multiple pregnancy
Diabetes
Late booker
High risk result: normal karyotype

18. Nuchal Translucency

19. 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%

20. Nuchal Translucency Nasal Bone Tricuspid Regurgitation
Fronto- Maxillary facial angle DV
Soft tissue thickness
Aberrant subclavian artery
Others?

21. Increased NT + Normal Karyotype
15%
46.2%
19.0%
64.5%
>6.4
30%
24.2%
10.1%
50.5%
50%
18.5%
3.4%
33.3%
70%
10.0%
2.7%
21.1%
A&W
Major
Anom
Fetal
Death
Chrom
Abn
NT (mm)‏

22. Case 1 44 year old grand multip Keen to avoid invasive testing
Pacific islander
All NVD
Keen to avoid invasive testing
NT 1.1mm = T21 risk 1:143

23. Case 1 Combined with 2nd trimester screen Risk T21 1:140 Risk T18 1:8
A-FP, Oestriol, free bHCG
Risk T21 1:140
Risk T18 1:8
Risk NTD 1:2900

24. Case 2 Primigravida age 29 Unplanned pregnancy but wanted
Epilepsy on Valproate 1000mg
Family history Talipes

25. Case 2 Wants Screening NT risk 1:2500 Routine 2nd trimester screening
Risk T21 1:5400
Risk T18 1:12000
Risk NTD 1:4

26. Case 2 Anomoly scan at 18/40 Difficult views
Lemon shape head and banana cerebellum
3D volumes = Sacral open NTD with cord tethering

27. 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?

30. 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

31. Advances in screening for trisomy 21
1st Trimester
free hCG
ONTD Screening
1st Trimester
Nuchal Translucency
free hCG
Combined
NB / TR / DV
Mat age
ADAM12 / PP13
'80 '85 '90 '95 '00 '05
Integrated
Sequential
Second trimester:
AFP Only
Total
hCG
1st Trimester
PAPP-A

32. Maternal Serum analytes
1st Trimester
PAPP-A
Free B-HCG
2nd Trimester
Alpha Fetoprotein ) )
Oestriol ) Triple Test)
Free B-HCG ) )
Inhibin-A )
Quadruple Test

33. First trimester screening for trisomy 21
Maternal serum free ß-hCG & PAPP-A 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 21 20 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) %
Trisomy 21
Normal
Normal
Detection rates at 12 weeks are similar to those at 16 weeks
Biochemical changes are independent of fetal NT thickness
NT, free ß-hCG and PAPP-A identifies 90% of cases for FPR of 5%

34. Second trimester screening for trisomy 21
Detection rates 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 ß-hCG & Inhibin A % 20 2 4 6 8 10 12 14 16 18
-3.5
-2.5
-1.5
-0.5
0.5
1.5
2.5
AFP & uE3 %
Tr 21
Tr 21
FPR 5%
59%
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 & IA
Cuckle 2001
DR 65%

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

36. 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

37. Combined first trimester screening
Author
Gest (wks) N
Detection rate
Krantz et al 2000
5,809
30/33 (91%)
Bindra et al 2002
14,383
74/82 (90%)
Spencer et al 2000; 2003
11,105
23/25 (92%)
Schuchter et al 2002
4,802
12/14 (86%)
Wapner et al. 2003
8,514
48/61 (79%)
Perni et al. 2006
4,883
20/22 (91%)
O’Leary et al. 2006
22,280
50/60 (83%)
Total
71776
257/297 (87%)
In meta-analysis of 77,000, 82% DR for 5% FPR

38. FASTER Trial: Trisomy 21 n=86, Normal n=32,269
FPR DR
Integrated: w NT & PAPP-A
15-18w AFP, hCG, E3, IA
4.9% 88%
Sequential: w NT & PAPP-A, ßhCG
Risk >1 in 30 positive(1.2%)
Risk <1 in 30:
15-18w AFP, hCG, E3, IA
5.1% 92%
In the SURUSS study and other centres, integrated has achieved higher DR (89-90%) for lower FPR (2.5%). Odds affected if + 1:9. The FASTER study has been criticised for it’s methodology.
Contingent: w 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%
Cuckle, Malone, Write et al 2008

39. Induced abortion-related maternal mortality:
USA 10 8 6
Deaths / 100,000 abortions 4 4
Miscarriage rates very similar amnio and cvs now 2
0.5
Gestation (wks))
Bartlett et al 2004

40. Why screen for aneuploidy? Options for Screening:
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

41. 2nd Trimester USS markers

42. 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

43. Hypoplastic NB (16/40<3.0mm)* (20/40<4.5mm)* Increased NF X17
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
Increased NF if previous NT less likely to indicate aneuploidy. Need to consider early hydrops or cystic hygroma
Bethune 2007 Aus Radiol 51;

44. 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;

45. Why screen for aneuploidy? Options for Screening:
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

46. New Tests ADAM 12 PAPP-A New markers?
Earlier gestation increases accuracy: 8/40
Repeated testing
New markers?

47. An extra serum marker: ADAM12
Performance <11 weeks:
Test Sens FPR
A % 1.5%
A12 / BhCG/ PaPPA 85% 1.5%
Triple biochem / NT 92% 0.8%
Laigaard et al / 2006

48. 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

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

50. Screening for Aneuploidy
Good reasoning
Complex haphazard introduction of tests
Tests initially hailed ‘100% accurate’
Have we opened Pandora’s box?