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Antenatal Screening. Dr Emma Parry CMFM emmap@adhb.govt.nz 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

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antenatal screening

Antenatal Screening

Dr Emma Parry CMFM

emmap@adhb.govt.nz

Clinical Director Maternal-Fetal Medicine

National Women’s Health

what is screening
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
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
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
slide5
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

Screening Tests

condition

absent

present

+ve

test

-ve

current standard screening programmes
Current Standard Screening Programmes
  • Infection:
    • Rubella
    • Hepatitis B
    • Syphilis
  • Malformation:
    • Aneuploidy
    • Structural
    • Syndromic
  • Red Cell Antibodies
variable screening programmes
Variable Screening Programmes
  • HIV
  • Thalassaemia
  • CMV
  • Smear
  • Swabs for infection
areas of difficulty
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
areas of difficulty1
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
Aneuploidy Screening
  • Evolving results
  • Soft markers on anomoly scan
  • Multiple pregnancy
  • Diabetes
  • Late booker
  • High risk result: normal karyotype
2 nd 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
slide13
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

slide14
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

aneuploidy screening1
Aneuploidy Screening
  • Evolving results
  • Soft markers on anomoly scan
  • Multiple pregnancy
  • Diabetes
  • Late booker
  • High risk result: normal karyotype
aneuploidy screening2
Aneuploidy Screening
  • Evolving results
  • Soft markers on anomoly scan
  • Multiple pregnancy
  • Diabetes
  • Late booker
  • High risk result: normal karyotype
nuchal translucency1
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 translucency2
Nuchal Translucency
  • Nasal Bone
  • Tricuspid Regurgitation
  • Fronto- Maxillary facial angle
  • DV
  • Soft tissue thickness
  • Aberrant subclavian artery
  • Others?
increased nt normal karyotype

NT (mm)‏

Chrom

Abn

Fetal

Death

Major

Anom

A&W

3.5-4.4

21.1%

2.7%

10.0%

70%

4.5-5.4

33.3%

3.4%

18.5%

50%

5.5-6.4

50.5%

10.1%

24.2%

30%

>6.4

64.5%

19.0%

46.2%

15%

Increased NT + Normal Karyotype
case 1
Case 1
  • 44 year old grand multip
    • Pacific islander
    • All NVD
  • Keen to avoid invasive testing
  • NT 1.1mm = T21 risk 1:143
case 11
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
Case 2
  • Primigravida age 29
  • Unplanned pregnancy but wanted
  • Epilepsy on Valproate 1000mg
  • Family history Talipes
case 21
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 22
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
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
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
slide30

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

maternal serum analytes
Maternal Serum analytes
  • 1st Trimester
    • PAPP-A
    • Free B-HCG
  • 2nd Trimester
    • Alpha Fetoprotein ) )
    • Oestriol ) Triple Test)
    • Free B-HCG ) )
    • Inhibin-A )

Quadruple Test

slide32

20

20

Trisomy 21

Trisomy 21

%

%

Normal

Normal

18

18

16

16

14

14

12

12

10

10

8

8

6

6

4

4

2

2

0

0

-3.5

-2.5

-1.5

-0.5

0.5

1.5

2.5

3.5

-3.5

-2.5

-1.5

-0.5

0.5

1.5

2.5

PAPP-A (SD)

Free ßhCG (SD)

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%
slide33

20

20

Tr 21

%

%

18

18

16

16

14

14

12

12

10

10

8

8

6

6

4

4

2

2

0

0

-3.5

-2.5

-1.5

-0.5

0.5

1.5

2.5

3.5

-3.5

-2.5

-1.5

-0.5

0.5

1.5

2.5

Free ß-hCG & Inhibin A

AFP & uE3

Cuckle 2001

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

59%

63%

63%

67%

72%

DR 65%

FPR 5%

Second trimester screening for trisomy 21

Detection rates

Tr 21

so what does it all mean
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
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
slide37

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

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

5.1% 92%

4.5% 91%

FASTER Trial: Trisomy 21 n=86, Normal n=32,269

FPR DR

Cuckle, Malone, Write et al 2008

slide38

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

slide39
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
2 nd trimester uss markers1
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
slide42
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

slide43
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

slide44
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
New Tests
  • ADAM 12
  • PAPP-A
    • Earlier gestation increases accuracy: 8/40
    • Repeated testing
  • New markers?
slide46

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%

Laigaard et al. 2003 / 2006

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