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  1. Prenatal Testing for Down Syndrome: Where Do We Stand Today? David B. Fox, MD Riverside Methodist Hospital

  2. Mental retardation Cardiac defects Leukemia Alzheimer's Visual/hearing impairment Intestinal malformations Shortened life span Down SyndromePhenotype abnormalities

  3. Why is Prenatal Testing Important? Peace of mind Education Emotional preparation Neonatal issues Termination

  4. Increased Risk of Fetal Aneuploidy • Previous fetus or child with autosomal trisomy or sex chromosome abnormality • One major or two minor fetal structural defects on ultrasound • Either parent with chromosomal translocation or inversion • Parental aneuploidy

  5. Is Prenatal Testing for Everyone?

  6. Prenatal Testing Screening versus Diagnosis First trimester versus Second trimester Serum and/or Ultrasound Low-risk versus High-risk Women

  7. Diagnostic Tests First trimester CVS TC 10 0/7 - 12 6/7 wks TA 10 0/7 - Term (if anterior placenta) Second trimester Amniocentesis 15 0/7 - Delivery

  8. Amniocentesis Pregnancy loss 1:300-1:500 Spotting or leakage 1-2% Needle injury - rare Infection - rare CVS Pregnancy loss - similar to amniocentesis (TA=TC) Spotting - up to 32% (TC) Leakage or infection - less than 0.5% Procedure-related Risks

  9. Screening Second trimester Maternal age Triple screen (AFP, HCG, estriol) Quad (Triple + inhibin) Ultrasound

  10. Gestational Age (wk) Maternal Age (y) Adapted from Nicolaides, AJOG, 2004

  11. “Age-Based” Screening Old story 5% of pregnant women > 35 yo 80% DS babies born to younger women New story 14% of pregnant women > 35 yo 70% DS born to younger women

  12. Second Trimester MSAFP Merkatz, 1984 Case report: Serendipitous discovery of low MSAFP in case of T18 led to discovery of low MSAFPassociated withfetal trisomy Sensitivity 20% for DS Age + MSAFP = 40% DS detection

  13. Second TrimesterTriple ScreenMSAFP + HCG + Estriol 65% Sensitivity 5%

  14. Second TrimesterQuadScreen Triple screen + inhibin 75 –80% DS detection 5% false positive rate

  15. Thickened nuchal fold Pyelectasis Echogenic bowel Short long bones Congenital anomaly Hypoplastic 5th digit Ear length Echogenic intracardiac focus Second TrimesterUltrasound Markers15-20 weeks

  16. 2nd Trimester Nasal Bone Screening AbsentNB 7 studies: 37% prevalence in T21, 0.9% in euploid ShortNB 6 studies: 48.2% prevalence in T21, 2.4% in euploid Short or AbsentNB 6 studies: 60% prevalence in T21, 1.4% in euploid

  17. Second TrimesterUltrasound Up to 75% of DS fetus will have a marker Therefore, 25% will have a normal ultrasound

  18. Problems with Second Trimester Ultrasound • Poor specificity • Subjective • Technical limitations • Variability of gestational age

  19. Aneuploidy Risk for Major Anomalies ADAPTED FROM SLIPP AND BENACERRAF (1990)

  20. First trimester Screening Nuchal translucency Free beta HCG PAPP-A CombinedNT and Serum

  21. Increased Nuchal Thickness

  22. Thickened NTwith Normal Karyotype

  23. Thickened NTwith Normal Karyotype

  24. Thickened NTwith Normal Karyotype

  25. First-Trimester or Second-Trimester Screening, or Both, for Down’s Syndrome (FASTER Trial) Malone et al, NEJM, 2005 15 U.S. Centers 38,167 women with singletons enrolled 117 cases of DS CRL 36-79mm (10 3/7 – 13 6/7 wks) NT + free beta HCG + PAPP-A (1:150) 15-18 wks Quad screen (1:300)

  26. FASTER Trial First trimester with 5% FP 11/12/13 (wks) NT 70/68/64 Free beta HCG/PAPP-A 70/67/65 Combined 87/85/82* *similar to Quad screen at 13 wks

  27. First and Second Trimester Sequential independent Sequential step-wise Serum integrated Fully integrated Sequential contingent

  28. Faster Trial Sequential independent 11/12/13 (wks) 1st: Combined NT/Serum 87%/85%/82% 2nd: Triple/Quad 69%/81% detection rates Calculateseparately Not recommended because (1) high false positive rate and (2) apriori risk not re-adjusted

  29. Faster TrialSequential Step-wiseFullyIntegrated First trimester NT/serum PLUS Second trimester Quad Blind patient to initial result until completion of Quad. Then give single risk. Exclude those with cystic hygoma. 11/12/13 (wks) Detection rate (%): 96/95/94

  30. FullyIntegrated “Potential” problems Both parts required Loss of follow-up (potential litigation) Physician/patient reluctance to withhold information Precludes early termination

  31. Contingent

  32. 1st Trimester“Absent” Nasal Bone • Usefulness controversial • 3 European studies: Down Syndrome sensitivity: 66.7-80% in high-risk women (0.2-1.4% FP rate) • Some studies show poor performance in general population

  33. Issues with Nasal Bone Screening • Correct technique • Significance of ethnicity AbsentNB seen in 2.8% Caucasians, 6.8% Asians, 10.4% Afro-Carribeans • Optimal population (HR vs. LR) • Optimal gestational age

  34. Nasal bone presentSonek, 2006

  35. Nasal bone absentSonek, 2006

  36. Pros Higher detection rate Earlier detection Safer termination NT identifies HR fetuses Less bonding More privacy Cons Cost ($600 – 700) Unnecessary termination Unwanted information First-Trimester Screening

  37. NTD Lab US: CRL 45 – 84 mm (11 1/7- 13 6/7 wks) Blood: 9 0/7 – 13 6/7 wks Instant Risk Assessment (IRA) Cost is $165 blood work/$513 Ultrasound DS 1:301 (90%) T18/13 1:150 (95%)

  38. “Invasive diagnostic testing for aneuploidy should be available to all women regardless of maternal age” ACOG, December 2007