Prenatal Testing for Down Syndrome: Where Do We Stand Today?

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Prenatal Testing for Down Syndrome Where Do We
Stand Today?

• David B. Fox, MD
• Riverside Methodist Hospital

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Down SyndromePhenotype abnormalities

• Mental retardation
• Cardiac defects
• Leukemia
• Alzheimer's

• Visual/hearing impairment
• Intestinal malformations
• Shortened life span

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Why is Prenatal Testing Important?

• Peace of mind
• Education
• Emotional preparation
• Neonatal issues
• Termination

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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

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Is Prenatal Testing for Everyone?
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Prenatal Testing

• Screening versus Diagnosis
• First trimester versus Second trimester
• Serum and/or Ultrasound
• Low-risk versus High-risk Women

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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

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Procedure-related Risks

• Amniocentesis
• Pregnancy loss 1300-1500
• Spotting or leakage
• 1-2
• Needle injury - rare
• Infection - rare

• CVS
• Pregnancy loss - similar to amniocentesis (TATC)
• Spotting - up to 32 (TC)
• Leakage or infection - less than 0.5

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Screening

• Second trimester
• Maternal age
• Triple screen (AFP, HCG, estriol)
• Quad (Triple inhibin)
• Ultrasound

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Gestational Age (wk)
12 16 40
20 1068 1200 1527
30 626 703 895
35 249 280 356
42 38 43 55
Maternal Age (y)
Adapted from Nicolaides, AJOG, 2004
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Age-Based Screening

• Old story
• 5 of pregnant women gt 35 yo
• 80 DS babies born to younger women
• New story
• 14 of pregnant women gt 35 yo
• 70 DS born to younger women

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Second Trimester MSAFP

• Merkatz, 1984
• Case report Serendipitous discovery of low
  MSAFP in case of T18 led to discovery of low
  MSAFP associated with fetal trisomy
• Sensitivity 20 for DS
• Age MSAFP 40 DS detection

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Second TrimesterTriple ScreenMSAFP HCG
Estriol
65
Sensitivity
5
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Second TrimesterQuad Screen

• Triple screen inhibin
• 75 80 DS detection
• 5 false positive rate

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Second TrimesterUltrasound Markers15-20
weeks

• Thickened nuchal fold
• Pyelectasis
• Echogenic bowel
• Short long bones

• Congenital anomaly
• Hypoplastic 5th digit
• Ear length
• Echogenic intracardiac focus

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2nd Trimester Nasal Bone Screening

• Absent NB
• 7 studies 37 prevalence in T21, 0.9 in
  euploid
• Short NB
• 6 studies 48.2 prevalence in T21, 2.4 in
  euploid
• Short or Absent NB
• 6 studies 60 prevalence in T21, 1.4 in euploid

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Second TrimesterUltrasound

• Up to 75 of DS fetus will have a marker
• Therefore, 25 will have a normal ultrasound

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Problems with Second Trimester Ultrasound

• Poor specificity
• Subjective
• Technical limitations
• Variability of gestational age

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Aneuploidy Risk for Major Anomalies
Defect Aneuploidy Risk Most Common Aneuploidies
Cystic hygroma 60-75 45X,21
Hydrops 30-80 13,21,18
Cardiac defect 5-30 13,18
AV canal defect 40-70 21
Duodenal atresia 20-30 21
ADAPTED FROM SLIPP AND BENACERRAF (1990)
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First trimester Screening

• Nuchal translucency
• Free beta HCG
• PAPP-A
• Combined NT and Serum

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Increased Nuchal Thickness
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Thickened NTwith Normal Karyotype
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Thickened NTwith Normal Karyotype
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Thickened NTwith Normal Karyotype
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• First-Trimester or Second-Trimester Screening, or
  Both, for Downs 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 (1150)
• 15-18 wks Quad screen (1300)

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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

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First and Second Trimester

• Sequential independent
• Sequential step-wise
• Serum integrated
• Fully integrated
• Sequential contingent

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Faster Trial

• Sequential independent
• 11/12/13 (wks)
• 1st Combined NT/Serum 87/85/82
• 2nd Triple/Quad 69/81 detection rates
• Calculate separately
• Not recommended because (1) high false positive
  rate and (2) a priori risk not re-adjusted

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Faster TrialSequential Step-wiseFully
Integrated

• 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

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Fully Integrated

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

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Contingent
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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

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Issues with Nasal Bone Screening

• Correct technique
• Significance of ethnicity
• Absent NB seen in 2.8 Caucasians, 6.8 Asians,
  10.4 Afro-Carribeans
• Optimal population (HR vs. LR)
• Optimal gestational age

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Nasal bone present Sonek, 2006
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Nasal bone absent Sonek, 2006
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First-Trimester Screening

• Pros
• Higher detection rate
• Earlier detection
• Safer termination
• NT identifies HR fetuses
• Less bonding
• More privacy

• Cons
• Cost (600 700)
• Unnecessary termination
• Unwanted information

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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 1301 (90) T18/13 1150 (95)

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Invasive diagnostic testing for aneuploidy
should be available to all women regardless of
maternal age

• ACOG, December 2007