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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?. 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

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  1. Antenatal Screening Dr Emma Parry CMFM emmap@adhb.govt.nz Clinical Director Maternal-Fetal Medicine National Women’s 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 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 performancex minimises false positives z minimises false negatives

  6. 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

  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. 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

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

  12. 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

  13. 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

  14. 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

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

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

  17. Nuchal Translucency

  18. 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%

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

  20. 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

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

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

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

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

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

  26. 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?

  27. 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

  28. 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

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

  30. 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%

  31. 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

  32. 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

  33. 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

  34. Combined first trimester screening

  35. 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

  36. 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

  37. 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

  38. 2nd Trimester USS markers

  39. 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

  40. 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

  41. 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

  42. 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

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

  44. 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

  45. 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

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

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