Antenatal Screening

1
Antenatal Screening

• Dr Emma Parry CMFM
• emmap_at_adhb.govt.nz
• Clinical Director Maternal-Fetal Medicine
• National Womens Health

2
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 populationare 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 performancex
minimises false positives z minimises
false negatives
6
Screening Tests
condition

• Sensitivity a/(ac) test
• Specificity d/(bd) test
• ve pred value a/(ab) cond
• -ve pred value d/(cd) cond
• Prevalence condition in population (ac)/(abc
  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 RiskSouthern
Alberta Centre for MFM
(NT clinic Astraia) (DELFIAXpress
Lifecycle) OSCAR
Woman arrives
Woman departs
Pre-test counselling
Post-test counselling
Free b HCG PAPP-A
Blood sample
Risk Assessment
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

• Absent NB X83
• Hypoplastic NB (16/40lt3.0mm)
• (20/40lt4.5mm)
• Increased NF X17
• Echogenic bowel X6
• Short femur X2.7
• Short humerus X7.5
• Pyelectasis X1

Bethune 2007 Aus Radiol 51218-225
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 51324-329
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

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Nuchal Translucency
19
Nuchal Translucency

• Designed for low risk women (lt40 years?)?
• USS measurement
• TA or TV
• Registered user (FMF)?
• Ongoing audit
• 113 to 136
• 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
22
Case 1

• 44 year old grand multip
• Pacific islander
• All NVD
• Keen to avoid invasive testing
• NT 1.1mm T21 risk 1143

23
Case 1

• Combined with 2nd trimester screen
• A-FP, Oestriol, free bHCG
• Risk T21 1140
• Risk T18 18
• Risk NTD 12900

24
Case 2

• Primigravida age 29
• Unplanned pregnancy but wanted
• Epilepsy on Valproate 1000mg
• Family history Talipes

25
Case 2

• Wants Screening
• NT risk 12500
• Routine 2nd trimester screening
• Risk T21 15400
• Risk T18 112000
• Risk NTD 14

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?

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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
1st Trimester PAPP-A
Total hCG
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

• 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
Tr 21
35
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 lt11500) 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 10-136 5,809 30/33 (91)
Bindra et al 2002 11-136 14,383 74/82 (90)
Spencer et al 2000 2003 10-136 11,105 23/25 (92)
Schuchter et al 2002 10-136 4,802 12/14 (86)
Wapner et al. 2003 10-136 8,514 48/61 (79)
Perni et al. 2006 11-136 4,883 20/22 (91)
OLeary et al. 2006 11-136 22,280 50/60 (83)
Total 71776 257/297 (87)
38
FASTER Trial Trisomy 21 n86, Normal
n32,269
FPR DR
Cuckle, Malone, Write et al 2008
39
Induced abortion-related maternal mortality USA
1988-1997
10
8
6
Deaths / 100,000 abortions
4
4
2
0.5
0
8 10 12 14 16 18 20 22
Gestation (wks))
Bartlett et al 2004
40

• 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

• Absent NB X83
• Hypoplastic NB (16/40lt3.0mm)
• (20/40lt4.5mm)
• Increased NF X17
• Echogenic bowel X6
• Short femur X2.7
• Short humerus X7.5
• Pyelectasis X1

Bethune 2007 Aus Radiol 51218-225
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 51324-329
45

• 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
• Earlier gestation increases accuracy 8/40
• Repeated testing
• New markers?

47
An extra serum marker ADAM12
Performance lt11 weeks Test Sens FPR A12 78
1.5 A12 / BhCG/ PaPPA 85 1.5 Triple biochem /
NT 92 0.8
Laigaard et al. 2003 / 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 RiskSouthern
Alberta Centre for MFM
(NT clinic Astraia) (DELFIAXpress
Lifecycle) OSCAR
Woman arrives
Woman departs
Pre-test counselling
Post-test counselling
Free b HCG PAPP-A
Blood sample
Risk Assessment
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 Pandoras box?