Prenatal Testing for Down

Syndrome: Where Do We
Stand Today?
David B. Fox, MD
Riverside Methodist Hospital
 Down Syndrome
Phenotype abnormalities

Mental retardation Visual/hearing

impairment
Cardiac defects
Intestinal malformations
Leukemia
Shortened life span
Alzheimer's
Why is Prenatal Testing
Important?

Peace of mind
Education
Emotional preparation
Neonatal issues
Termination
 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
Is Prenatal Testing for
Everyone?
 Prenatal Testing

Screening versus Diagnosis

First trimester versus Second trimester

Serum and/or Ultrasound

Low-risk versus High-risk Women

 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
 Procedure-related Risks

Amniocentesis CVS

 Pregnancy loss
 Pregnancy loss -
similar to
1:300-1:500
amniocentesis
 Spotting or leakage (TA=TC)
1-2%  Spotting - up to 32%
 Needle injury - rare (TC)
 Infection - rare
 Leakage or infection
- less than 0.5%
 Screening
Second trimester

Maternal age
Triple screen (AFP, HCG, estriol)
Quad (Triple + inhibin)
Ultrasound
 Gestational Age (wk)
12 16 40

Maternal
20 1068 1200 1527
Age (y) 30 626 703 895
35 249 280 356
42 38 43 55

Adapted from Nicolaides, AJOG, 2004

“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
 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

 Second Trimester
Triple Screen
MSAFP + HCG + Estriol
100%
90%
80%
65% 70%
60%
50%
Sensitivity 40%
30%
20%
10%
0%
False Positive

5%
 Second Trimester
Quad Screen

Triple screen + inhibin

75 –80% DS detection

5% false positive rate

 Second Trimester
Ultrasound Markers
15-20 weeks
Thickened nuchal fold Congenital anomaly

Pyelectasis Hypoplastic 5th digit

Echogenic bowel Ear length

Short long bones Echogenic intracardiac

focus
 2 Trimester
nd

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
 Second Trimester
Ultrasound

Up to 75% of DS fetus will have a marker

Therefore, 25% will have a normal ultrasound

Problems with Second Trimester
Ultrasound

 Poor specificity

 Subjective

 Technical limitations

 Variability of gestational age

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

Nuchal translucency
Free beta HCG
PAPP-A

Combined NT and Serum

Increased Nuchal Thickness
 Thickened NT
with Normal Karyotype
 Thickened NT
with Normal Karyotype
 Thickened NT
with Normal Karyotype
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)
 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

 First and Second Trimester

Sequential independent

Sequential step-wise
Serum integrated
Fully integrated
Sequential contingent
 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
 Faster Trial
Sequential Step-wise
Fully 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
 Fully Integrated
“Potential” problems
Both parts required

Loss of follow-up (potential litigation)

Physician/patient reluctance to withhold information

Precludes early termination

 Contingent

First-trimester Screen

High Risk Intermediate Risk Low Risk

Offer CVS Quad Screen No Further Testing

Offer Amino if HR
 1 Trimester
st

“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
 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
Nasal bone present
Sonek, 2006
Nasal bone absent
Sonek, 2006
 First-Trimester Screening
 Pros  Cons
 Higher detection rate  Cost ($600 – 700)
 Earlier detection
 Unnecessary termination
 Safer termination
 Unwanted information
 NT identifies HR fetuses

 Less bonding

 More privacy
 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%)

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

ACOG, December 2007