First and Second Trimester Trisomy Screening

1. First and Second Trimester Trisomy Screening J. Christopher Glantz

2. Trisomies 21, 18, and 13 • Incidence (live births) • 21: 1/6-800 18: 1/7,000 13: <1/10,000 • Trimester Frequency: First>Second>Third • Spontaneous and induced losses • 20-30% for 21, 40% for 13, 66% for 18 • Mental Retardation • Congenital anomalies

3. Risk Factors • Congenital anomalies • Maternal age • Multiple gestation • Previous aneuploidy (patient or family) • 70% have no identifiable risk factors

4. Screening Identifying in apparently healthy individuals those who are sufficiently at risk of a specific disorder as to justify a subsequent diagnostic test or procedure

5. (-) (+) Diagnostic versus Screening No overlap: Positive test is abnormal Overlap: Positive test could be normal or abnormal

6. 95% False Positives 98% Sensitivity 99% Specificity 50% Sensitivity 33% Sensitivity 5% Specificity 6% False Positives (94% Specificity) 1% False Positives Sensitivity & Specificity Unaffected Affected

7. Essential Elements of Screening • It is NOT diagnostic! • Screen positive rates and PPV depend on a priori population risk and the desired detection rate (sensitivity) • An acceptable diagnostic test or procedure must be available for screen-positives • Should be cost effective and low risk • A treatment must be available for true positives

8. Second Trimester Screening (Triple/Quadruple Marker) • 65-70% detection with 5% false positives • Incorporating the Genetic Sonogram (“soft signs”) may lower the false positive rate • Information on open defects • NTD, ventral wall, etc. • Only 50% of Finger Lakes women have triple marker screening

9. Problems with Second Trimester Screening • False positives • Patient anxiety • Lessened by better pre-test counseling • Unnecessary amniocentesis • Procedural loss 0.5% • Late diagnosis • Psychologically and technically more difficult to terminate • Suboptimal sensitivity

10. Advantages to 1st Trimester Screening • Earlier diagnosis • Pregnancy less obvious, more private • May be less bonding • Pregnancy termination easier and safer • Surveys: Many patients prefer it • CAVEAT: Need test to have high sensitivity and low false positives • Account for spontaneous (and procedural) losses • Preferentially identify high risk for loss?

11. First Trimester Nuchal Translucency • Lymphatic obstruction or distensible tissue • Cystic hygroma or precursor • May resolve or persist • Associated with increased risk of trisomy • Also with cardiac anomalies (5-10x RR) • Normal values depend on gestational age • No one cut point for all pregnancies (3±? mm) • The wider the translucency, the higher the risk

12. Amnion Skin Nuchal Translucency (NT)

13. Nuchal Translucency Results • 30 studies including 316,000 patients • Trisomy 21 frequency: 0.1-1.6% • Detection rate (population dependent) • Range: 29-100% (mean 77%) • False positive: 0.3-12% (mean 6%) • PPV: 2-50% : training disparity? • Issues with T-21 freq, ascertainment, losses Malone & D’Alton, 2003

14. Biochemical Markers • Pregnancy associated plasma protein A (PAPP-A) • Protease for IGF binding protein • Decreased with trisomies • Human chorionic gonadotropin (ßhCH) • Increased with 21 and 18, decreased with 13 • Free versus Total? • PAPP-A and ßhCG for Trisomy 21 • 60% sensitive, 5% false positive rate

15. Distribution of PAPP-A Measurements Down Syndrome Unaffected 42% 5% 0.2 0.5 1 2 7 PAPP-A (MoM)

16. Distribution of First Trimester Free bhCG Measurements Down Unaffected Syndrome 28% 5% 0.2 0.5 1 2 5 10 Free-beta (hCG) MoM

17. Are Cute Acronyms Required For NIH Funding? (CAR Fund) • VIP • Vaginal Infections in Pregnancy • RADIUS • Routine Antenatal Diagnostic Imaging with UltraSound • MR FIT • Multiple Risk Factor Intervention Trial • PROVE IT • PRavastatin or atrOVastatin Evaluation and Infection Therapy • COOL AID • COOLing for Acute Ischemic brain Damage

18. Ultrasound Acronyms in Trisomy Screening • Acceptable: SURUSS • Serum, URine, Ultrasound Screening Study • Tortured: BUN—??? • First trimester maternal serum Biochemistry and fetal Nuchal translucency screening study • FTMSBFNTSS • MISnamed and Already TAKEn (MISTAKE): FASTER • First And Second Trimester Evaluation of Risk • Publication still pending despite years of hype • Fibrinolytic & Aggrastat ST Elevation Resolution • First Albarelix Study for Treating Endometriosis Rapidly

19. First Trimester Screening with NT and Biochemistry • Eight studies with 85,000 patients • Trisomy 21 frequency: 0.2-0.9% • Detection rate (population dependent) • Range: 62-92% (mean 82%) • False positive: 3-8% (mean 5%) • PPV: 5% Malone & D’Alton, 2003

20. ACOG July 2004 First and second trimester screening have comparable detection and false positive rates. Criteria for Offering 1st Trimester Screening: Appropriate ultrasound training and QA Comprehensive counseling to women (options, risks, benefits) Access to appropriate diagnostic testing for positive screens - CVS in first trimester

21. Disadvantages of First Trimester Screening • Patients must present early • Does not assess neural tube defects • CVS is less available, slightly higher risk, and not as accurate as amnio • Prolonged anxiety if no diagnostic test • Difficulties with multiple gestations • First trimester screening may identify fetuses destined to abort spontaneously

22. Approaches to Screening • Nuchal translucency alone • First trimester biochemistry alone • Combined: NT and first trimester biochemistry • Integrated first and second trimester • No result until both tests done • Sequential first and second trimester • Results known after first test • Second trimester screening alone

23. Integrated 1st and 2nd Trimester Screening • NT/PAPP-A in the 1st trimester and ßhCG, AFP, estriol, and inhibin in the 2nd trimester • Detection rates 85-90-93% • False positive rates 1-2-5%, respectively • 1% higher if NT not used • Most cost effective • Results not available until the 2nd trimester • Ethics of not sharing abnormal 1st trim results SURUSS, 2003

24. Sequential 1st and 2nd Trimester Screening • 4300 patients who were informed of 1st trimester results and chose also to have 2nd trimester screening • High (98%) sensitivity but poor specificity • 17% had positive 1st or 2nd trimester screens • How to interpret second test (or genetic sonogram) in light of normal first test? • Changes a priori risks BUN, 2004

25. Approximate Detection Rates Various studies 5% False Positives

26. SURUSS: Screen-Positive Rates for 85% Trisomy 21 Detection

27. Finger Lakes Women • Combined test and CVS available through SMH • Insurance issues persist • Offer patients various options? • May depend on when patient presents for care • Integrated most efficient but later diagnosis • Unresolved issues with sequential testing • Combined test for aneuploidy, then MSAFP for open defects

29. NT Technique • 11-14 weeks (CRL 45-84 mm) • High magnification, 3 measurements • Sagittal midline, mid-position neck • Proper caliper placement • Practice makes perfect • May take up to 20 minutes • Best labs get 80-99%

30. First Trimester NT Measurements

31. More Acronyms • Orlowsi & Christensen 2002 • Coercive nature of research acronyms • CURE, HOPE, LIFE, SAFER, MIRACLE, ALIVE • ASSENT, GREAT, GUARANTEE, DESIRE, WISE • ASS, DEAD, DEATH • “A Surefire Cure for Cancer” Study • T.O. Cheng: 27 publications about acronyms