The document discusses strategies for prenatal diagnosis and screening for fetal aneuploidy. It describes calculating patient-specific risk by combining a woman's background risk with likelihood ratios obtained from multiple screening tests, which increases or decreases the risk. Screening tests have improved over time, with first trimester tests like nuchal translucency and blood markers now detecting over 90% of trisomies. All women should have the option of diagnostic testing regardless of age.

1. Contemporary
Strategy for
Prenatal Diagnosis
Professor Hassan Nasrat FRCS, FRCOG
The Fetal Medicine Clinic
The First Clinic
JUCOG 2013
Sunday, July 28, 13

2. Maternal characteristics
History
Biophysical finding from US
Findings from biochemical tests
Current Objective Of Prenatal Care Is To
Define Patient Specific Risk For Pregnancy
Complications At Early Stage.
Through Combining Data Data From:
Sunday, July 28, 13

3. Diagnosisof aneuploidy
Sunday, July 28, 13

4. “ Maternal Age Of 35 Should No Longer Be
Used By Itself As A Cut-off To Determine Who
Is Offered Screening Versus Who Is Offered
Invasive Diagnostic Testing,"
“All Pregnant Women, Regardless Of Their Age,
Should Have The Option Of Diagnostic Testing”
2007
Sunday, July 28, 13

5. Diagnosis
of
aneuploidy
Screening
For
aneuploidy
Sunday, July 28, 13

6. Diagnosis
of
aneuploidy
Assessment
of
patient
specific
risk
for
aneuploidy
Screening
For
aneuploidy
Sunday, July 28, 13

7. Diagnosis
of
aneuploidy
Non-­‐invasive
Methods
Assessment
of
patient
specific
risk
for
aneuploidy
Screening
For
aneuploidy
Sunday, July 28, 13

8. Diagnosis
of
aneuploidy
Non-­‐invasive
Methods
Invasive
Methods
Assessment
of
patient
specific
risk
for
aneuploidy
Screening
For
aneuploidy
Sunday, July 28, 13

9. Strategies
of
Screening
For
aneuploidy
Sunday, July 28, 13

10. 0 25 50 75 100
95.00
90.00
87.00
82.00
91.00
81.00
75.00
87.00
69.00
75.00
21.001985-
1990
1991-
1995
1996-
2010
Maternal Serum AFP
Genetic Ultrasound
Maternal Serum Triple Marker
Genetic Ultrasound
First Trimester NT
Maternal Serum QUAD marker
Genetic Ultrasound
First Trimester NT
First Trimester NT and Serum Plus Selective NT,TR, and DV
First Trimester NT and Serum
First Trimester NT and Serum +Second-trimester QUAD
History of Detection of Fetal Trisomy
Sunday, July 28, 13

11. PRINCIPLES
OF
SCREENING
Important
proper+es
of
a
screening
test
are
its
sensi+vity,
specificity,
and
predic+ve
values
nega+ve
and
posi+ve.
Sunday, July 28, 13

12. PRINCIPLES
OF
SCREENING
Important
proper+es
of
a
screening
test
are
its
sensi+vity,
specificity,
and
predic+ve
values
nega+ve
and
posi+ve.
The
sensi(vity
and
specificity
cannot
be
used
to
es+mate
the
probability
of
the
disease
in
an
individual.
Sunday, July 28, 13

13. PRINCIPLES
OF
SCREENING
Important
proper+es
of
a
screening
test
are
its
sensi+vity,
specificity,
and
predic+ve
values
nega+ve
and
posi+ve.
The
sensi(vity
and
specificity
cannot
be
used
to
es+mate
the
probability
of
the
disease
in
an
individual.
Posi(ve
and
nega(ve
predic(ve
are
dependent
on
the
prevalence
of
the
disease
Sunday, July 28, 13

14. PRINCIPLES
OF
SCREENING
Important
proper+es
of
a
screening
test
are
its
sensi+vity,
specificity,
and
predic+ve
values
nega+ve
and
posi+ve.
The
sensi(vity
and
specificity
cannot
be
used
to
es+mate
the
probability
of
the
disease
in
an
individual.
Posi(ve
and
nega(ve
predic(ve
are
dependent
on
the
prevalence
of
the
disease
The
likelihood
ra(o
are
independent
of
disease
prevalence
and
integrate
the
sensi+vity
and
specificity
of
screening
tests
Sunday, July 28, 13

15. The
likelihood
ra(o
Indicate by how much a given test result
increases or decreases the probability of
developinga condition.
Sunday, July 28, 13

16. Every
woman
has
a
background
(priori)
risk
of
having
a
chromosomal
defective
baby.
Calculation
of
Patient
Specific
RISK
“Using
Positive
&
Negative
Likelihood
Ratio”
Sunday, July 28, 13

17. Every
woman
has
a
background
(priori)
risk
of
having
a
chromosomal
defective
baby.
Calculation
of
Patient
Specific
RISK
“Using
Positive
&
Negative
Likelihood
Ratio”
The
risk
may
increase
or
decrease
based
on
the
presence
(or
absence)
of
certain
marker
(s)
Sunday, July 28, 13

18. Every
woman
has
a
background
(priori)
risk
of
having
a
chromosomal
defective
baby.
Calculation
of
Patient
Specific
RISK
“Using
Positive
&
Negative
Likelihood
Ratio”
×
The
risk
may
increase
or
decrease
based
on
the
presence
(or
absence)
of
certain
marker
(s)
The
Background
“Priori
Risk”
Sunday, July 28, 13

19. Every
woman
has
a
background
(priori)
risk
of
having
a
chromosomal
defective
baby.
Calculation
of
Patient
Specific
RISK
“Using
Positive
&
Negative
Likelihood
Ratio”
×
The
Likelihood
ratio
as
Calculated
from
a
given
marker
The
risk
may
increase
or
decrease
based
on
the
presence
(or
absence)
of
certain
marker
(s)
The
Background
“Priori
Risk”
Sunday, July 28, 13

20. Every
woman
has
a
background
(priori)
risk
of
having
a
chromosomal
defective
baby.
Calculation
of
Patient
Specific
RISK
“Using
Positive
&
Negative
Likelihood
Ratio”
×
The
Likelihood
ratio
as
Calculated
from
a
given
marker
a
new
priori
Posterior
Risk
For
the
next
test
The
risk
may
increase
or
decrease
based
on
the
presence
(or
absence)
of
certain
marker
(s)
The
Background
“Priori
Risk”
Sunday, July 28, 13

21. Every
woman
has
a
background
(priori)
risk
of
having
a
chromosomal
defective
baby.
Calculation
of
Patient
Specific
RISK
“Using
Positive
&
Negative
Likelihood
Ratio”
×
The
Likelihood
ratio
as
Calculated
from
a
given
marker
a
new
priori
Posterior
Risk
For
the
next
test
The
different
tests
are
independent
The
risk
may
increase
or
decrease
based
on
the
presence
(or
absence)
of
certain
marker
(s)
The
Background
“Priori
Risk”
Sunday, July 28, 13

22. 0.6 0.4 2.0
LR=1.7 LR=10.6 LR=2.0
AFP(MOM) UE3(MOM) hCG(MOM)
Age Risk
30 years
1:900
Likelihood Ratio
AFP UE3 hCG
1.7 × 10.4 × 2.0
× =
Adjusted
Risk
1:25
Normal
DS
Calculations
of
LRs
for
three
analytes.
At
a
MSAFP
level
of
0.6
MoM,
approximately
twice
as
many
fetuses
with
Down
syndrome
are
at
this
level
than
chromosomally
normal
fetuses.
Therefore,
the
LR
for
Down
syndrome
at
a
MSAFP
level
of
0.6
MoM
is
1.7.
Sunday, July 28, 13

23. Every woman has a background or a
priori risk that her fetus/baby has a
chromosomal defect.
A new individual “patient-specific”
risk is calculated by multiplying the
priori risk with a series of likelihood
ratios obtained from screening tests.
Summary
Sunday, July 28, 13

24. Screening for Fetal Aneuploidy
Sunday, July 28, 13

25. Screening for Fetal Aneuploidy
Maternal Age
Previous History Tests
Sunday, July 28, 13

26. Screening for Fetal Aneuploidy
Maternal Age
Previous History Tests
Biochemical
Tests
Sunday, July 28, 13

27. Screening for Fetal Aneuploidy
Maternal Age
Previous History Tests
Biochemical
Tests
Sonography Findings
Sunday, July 28, 13

28. Screening for Fetal Aneuploidy
Maternal Age
Previous History Tests
Sonography Findings
Sunday, July 28, 13

29. Screening for Fetal Aneuploidy
Maternal Age
Previous History Tests
Sunday, July 28, 13

30. Risk
of
Aneuploidy
based
on
Maternal
Age
and
Gestational
Week
Sunday, July 28, 13

31. Sunday, July 28, 13

32. The
Risk
Is
Almost
Constant
At
Ages
15
To
25
Rises
Slowly
Between
25
To
35
Increases
Approximately
4-­‐fold
From
Ages
35
To
40
And
10-­‐fold
From
Ages
40
To
45;
Aneuploidy
and
Maternal
Age
Sunday, July 28, 13

33. The
Risk
Is
Almost
Constant
At
Ages
15
To
25
Rises
Slowly
Between
25
To
35
Increases
Approximately
4-­‐fold
From
Ages
35
To
40
And
10-­‐fold
From
Ages
40
To
45;
Aneuploidy
and
Maternal
Age
Sunday, July 28, 13

34. The
Risk
Is
Almost
Constant
At
Ages
15
To
25
Rises
Slowly
Between
25
To
35
Increases
Approximately
4-­‐fold
From
Ages
35
To
40
And
10-­‐fold
From
Ages
40
To
45;
Aneuploidy
and
Maternal
Age
Sunday, July 28, 13

35. Risk
of
Aneuploidy
based
on
Previous
Trisomy
Sunday, July 28, 13

36. Previous Trisomy 21 increases the risk of recurrence
by a factor of 0.75% above the maternal and
gestational age-related risk for trisomy 21 at the
time of testing.
A
previous
trisomy
21:
✦For
35
years
old
woman
the
risk
at
12
weeks
of
gestation
increases
from
1
in
249
(0.40%)
to
1
in
87
(1.15%).
✦For
25
years
old
woman
the
risk
increases
from
1
in
946
(0.106%)
to
1
in
117
(0.856%).
Sunday, July 28, 13

37. The risk for trisomies increases with maternal age.
The risk of Turner syndrome and triploidy does not change
with maternal age.
The earlier the gestation, the higher the risk for chromosomal
defects.
 A previous fetus or baby with a trisomy increases the risk in a
current pregnancy by 0.75% over a priori risk.
Summary
Sunday, July 28, 13

38. Screening for Fetal Aneuploidy
Maternal Age
Previous History Tests
Sunday, July 28, 13

39. Screening for Fetal Aneuploidy
Maternal Age
Previous History Tests
Biochemical
Tests
Sunday, July 28, 13

40. In order to take account of sources of variation, the
concentration of each marker is expressed as a multiple
of the median for pregnancies of the same gestational
age (MoM).
Sunday, July 28, 13

41. cted
uE3
(MoM)
UnaffectedDown’s syndrome
Down’s syndromeUnaffectedfected
Down’s syndrome Unaffected
AFP (MoM) uE3
(MoM)
UnaffectedDown’s syndrome
Nuchal translucency (MoM)
Down’s syndromeUnaffectedDown’s syndrome
PAPP-A (MoM)
Unaffected
Down’s syndrome Unaffected
AFP (MoM) uE3
(MoM)
UnaffectedDown’s syndrome
Nuchal translucency (MoM)
Down’s syndromeUnaffectedDown’s syndrome
PAPP-A (MoM)
Unaffected
Nuchal tra
Unaffected
Unaffected
Inhibin-A (MoM)
Down’s syndrome
PAPP-A (MoM)
Unaffected
Unaffected Down’s
syndrome
free ß
9
Down's
syndrome
Unaffected
Inhibin-A (MoM)
Unaffected Down’s
syndrome
free ß-hCG (MoM)
Down’s syndrome Unaffected
AFP (MoM) uE3
(MoM)
UnaffectedDown’s syndrome
Nuchal translucency (MoM)
Down’s syndromeUnaffected
Down's
syndrome
Unaffected
Down’s syndrome
PAPP-A (MoM)
Unaffected
Unaffected Down’s
syndrome
UnaffectedD Syndrome
UnaffectedD Syndrome
D SyndromeUnaffected
Unaffected Unaffected
Unaffected D Syndrome
D Syndrome D Syndrome
Sunday, July 28, 13

42. ✦Maternal Weight:
✦Ethnic Group:
✦In Vitro Fertilization (IVF):
✦Insulin Dependent Diabetes Mellitus (IDDM):
✦Smoking:
✦Previous affected pregnancies
✦Vaginal bleeding
✦Results of screening in a previous pregnancy
FACTORS AFFECTING THE TEST
Sunday, July 28, 13

43. THREE SCREENING OPTIONS
2nd Trimester
Quad
1st Trimester
Combined Test
1st and 2nd Trimester
Fully Integrated Test
Serum Integrated
Stepwise Sequential Contingent
Sequential Screen
Sunday, July 28, 13

44. THREE SCREENING OPTIONS
1st Trimester
Combined Test
Sunday, July 28, 13

45. 1...9 10 11 12 13 14 15 16 17 18
19 20......40
10 to 14 wks
Blood Draw
COMBINED
INTEGRATED
11 to 14 wks
Nuchal
Translucency
PAPPA-A
hCG
+Measurement of CRL
Sunday, July 28, 13

46. COMBINED TEST
1
Blood Drawn: 10 Weeks 0 days to 13 weeks 6
days
Test: PAPPA-A and hCG
2 ULTRASOUND: 11 Weeks 2 days to 14 weeks 2
days Test: Measure Nuchal Translucency
First Trimester
Cut off (mid-
trimester risk)
False
Positive
Rate
Detection
Rate
1:80 2.02% 72.57%
1:100 2.54% 74..99%
1:120 3.03% 76.89%
Risk
Assessment
•Trisomy 21
•Trisomy 18
Sunday, July 28, 13

47. 0
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
90.00
100.00
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 45
Combined Test
Overall Detection Rate 85%
MATERNAL AGE
DETECTION RATE OF TRISOMY 21 BASED ON MATERNAL
AGE
85%
50%
Sunday, July 28, 13

48. THREE SCREENING OPTIONS
2nd Trimester
Quad
1st Trimester
Combined Test
Sunday, July 28, 13

49. 1...9 10 11 12 13 14 15 16 17 18 19 20......40
15 to 20wks
Blood Draw
Quad Test
Quad
AFP
hCG
Ue3
Inhibin
Sunday, July 28, 13

50. QUAD TEST
0
25
50
75
100
80.00
67.00
97.00
80.00
85.00
60.00
Tri 21 Tri 18 Anecephaly Spina Bifida Abd W D SLOS
Detection Rate
Sunday, July 28, 13

51. What Does A Negative Test Miss?
0
10
20
30
40
20
33
3
20
15
40
Tri 21 Tri 18 Anecephaly Spina Bifida Abd W D SLOS
Percent of Birth Defects Not Detected
Sunday, July 28, 13

52. THREE SCREENING OPTIONS
2nd Trimester
Quad
1st Trimester
Combined Test
1st and 2nd Trimester
Fully Integrated Test
Serum Integrated
Sequential Screen
Contingent Screen
Sunday, July 28, 13

53. 1...9 10 11 12 13 14 15 16 17 18 19 20......40
10 to 14 wks
Fully Integrated
Measurement of CRL
+
PAPPA-A
hCG
11 to 14 wks
Nuchal
Translucency
Sunday, July 28, 13

54. 1...9 10 11 12 13 14 15 16 17 18 19 20......40
10 to 14 wks
Results are Reported after The Second Blood Test
15 to 20 wks
Fully Integrated
AFP
hCG
Ue3
InhibinMeasurement of CRL
+
PAPPA-A
hCG
11 to 14 wks
Nuchal
Translucency
Sunday, July 28, 13

55. 1...9 10 11 12 13 14 15 16 17 18 19 20......40
10 to 14 wks
Serum Integrated
Measurement of CRL
+
PAPPA-A
hCG
Sunday, July 28, 13

56. 1...9 10 11 12 13 14 15 16 17 18 19 20......40
10 to 14 wks
Results are Reported after The Second Blood Test
15 to 20 wks
Serum Integrated
AFP
hCG
Ue3
InhibinMeasurement of CRL
+
PAPPA-A
hCG
Sunday, July 28, 13

57. First-trimester Screening
Screen
Positive
CVS
Final Result
incorporate
1st and 2nd
results
Screen
Negative
QUAD
Sequential Screen
Sunday, July 28, 13

58. First-trimester Screening
Very High
Risk >1 in 50
CVS
Contingent Screen
Intemediate
Risk
(1in 50 to 1
in 1000
QUAD
Low Risk
<1 in 2000
NoAdditional
Test
Sunday, July 28, 13

59. First
Trimester
Second
Trimester
1st & 2nd
Trimester
Sunday, July 28, 13

60. 0
25
50
75
100
First
Trimester
Second
Trimester
1st & 2nd
Trimester
Sunday, July 28, 13

61. 0
25
50
75
100
75
First
Trimester
Second
Trimester
1st & 2nd
Trimester
Sunday, July 28, 13

62. 0
25
50
75
100
75
85
NT NT
+
PAPP-A
&
β-hCG
First
Trimester
Second
Trimester
1st & 2nd
Trimester
Sunday, July 28, 13

63. 0
25
50
75
100
75
85
75
NT
AFP
+
Ue3
&
β-hCG
NT
+
PAPP-A
&
β-hCG
First
Trimester
Second
Trimester
1st & 2nd
Trimester
Sunday, July 28, 13

64. 0
25
50
75
100
75
85
75
NT
AFP
+
Ue3
&
β-hCG
NT
+
PAPP-A
&
β-hCG
First
Trimester
Second
Trimester
1st & 2nd
Trimester
Sunday, July 28, 13

65. 0
25
50
75
100
75
85
75
NT
AFP
+
Ue3
&
β-hCG
NT
+
PAPP-A
&
β-hCG
85
AFP
+
Ue3
&
β-hCG
&
Inhibin
“QUAD“
First
Trimester
Second
Trimester
1st & 2nd
Trimester
Sunday, July 28, 13

66. 0
25
50
75
100
75
85
NT NT
+
PAPP-A
&
β-hCG
85
AFP
+
Ue3
&
β-hCG
&
Inhibin
“QUAD“
First
Trimester
Second
Trimester
1st & 2nd
Trimester
Sunday, July 28, 13

67. 0
25
50
75
100
75
85
NT NT
+
PAPP-A
&
β-hCG
85
AFP
+
Ue3
&
β-hCG
&
Inhibin
“QUAD“
95
NT
+
PAPP-A
&
β-hCG
“QUAD”
First
Trimester
Second
Trimester
1st & 2nd
Trimester
Sunday, July 28, 13

68. 0
25
50
75
100
75
85
NT NT
+
PAPP-A
&
β-hCG
85
AFP
+
Ue3
&
β-hCG
&
Inhibin
“QUAD“
95
NT
+
PAPP-A
&
β-hCG
“QUAD”
What
if
NT
is
Not
Available?
First
Trimester
Second
Trimester
1st & 2nd
Trimester
Sunday, July 28, 13

69. 0
25
50
75
100
75
85
NT NT
+
PAPP-A
&
β-hCG
85
AFP
+
Ue3
&
β-hCG
&
Inhibin
“QUAD“
95
85
NT
+
PAPP-A
&
β-hCG
“QUAD”
PAPP-A
&
β-hCGWhat
if
NT
is
Not
Available?
First
Trimester
Second
Trimester
1st & 2nd
Trimester
“QUAD”
Sunday, July 28, 13

70. 0
10
20
30
40
50
60
70
80
90
100
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 45
Fully Integrated
Overall Detection Rate 95%
MATERNAL AGE
DETECTION RATE OF TRISOMY 21
BASED ON MATERNAL AGE
90%
50%
Sunday, July 28, 13

71. 0
25
50
75
100
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 45
Serum Integrated
Overall Detection Rate 85%
MATERNAL AGE
DETECTION RATE OF TRISOMY 21 BASED ON
MATERNAL AGE
80%
72%
Sunday, July 28, 13

72. 0
10
20
30
40
50
60
70
80
90
100
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 45
Fully Integrated
Overall Detection Rate 95%
MATERNAL AGE
DETECTION RATE OF TRISOMY 21
BASED ON MATERNAL AGE
90%
50%
Sunday, July 28, 13

73. 0
10
20
30
40
50
60
70
80
90
100
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 45
Fully Integrated
Overall Detection Rate 95%
MATERNAL AGE
DETECTION RATE OF TRISOMY 21
BASED ON MATERNAL AGE
90%
50%
Sunday, July 28, 13

74. 0
10
20
30
40
50
60
70
80
90
100
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 45
Fully Integrated
Overall Detection Rate 95%
MATERNAL AGE
DETECTION RATE OF TRISOMY 21
BASED ON MATERNAL AGE
90%
50%
HOW?
90+%
Sunday, July 28, 13

75. Screening for Fetal Aneuploidy
Maternal Age
Previous History Tests
Biochemical
Tests
Sunday, July 28, 13

76. Screening for Fetal Aneuploidy
Maternal Age
Previous History Tests
Biochemical
Tests
Sonography Findings
Sunday, July 28, 13

77. FIRST TRIMESTER
SECOND TRIMESTER
Sunday, July 28, 13

78. 1ST TRIMESTER
SCREENING
Sunday, July 28, 13

79. Nasal Bone
Tricuspid Regurgitation
Ductus Venousus
Figure 3 Four-chamber view illustrating an endocardial cushion
defect in which a ventricular (VSD) and atrial (ASD) septal defect
are present. LA, left atrium; LV, left ventricle; RA, right atrium;
RV, right ventricle.
SUGGESTED USE OF FETAL
ECHOCARDIOGRAPHY AS PART OF THE
GENETIC SONOGRAM GIVEN CURRENT
SCREENING TECHNOLOGIES
At present, common screening tests for trisomy 21 may
include any of the following: (1) first-trimester combined
NT and serum screening, (2) first-trimester combined
NT and serum screening plus second-trimester QUAD
screening, (3) first-trimester serum and second-trimester
Genetic sonography as an adjunct to first-trimester NT
and serum and/or second-trimester serum screening
When genetic sonography was first introduced in the
early 1990s it was an option for screening for trisomy
21 in women less than 35 years of age for two reasons:
(1) the detection rate was similar to or higher than that
using MSAFP screening, and (2) the ultrasound exam only
required measurements of the biparietal diameter, femur
length and nuchal skin fold (Table 1). However, as more
analytes were added, second-trimester maternal serum
(triple and QUAD) screening increased the detection
rate for trisomy 21, was easier to use, and did not
require the specialized ultrasound skills needed to keep
the genetic sonogram comparable in terms of detection
rates (Table 2).
Investigators have reported the use of genetic sono-
graphy as an adjunct to other screening protocols.
In 2001, Roberto Romero and I11
reported offer-
ing genetic sonography to women considered to be
at moderate risk (1 : 190–1 : 1000) for trisomy 21
Figure 4 Four-chamber view illustrating a ventricular septal defect (VSD) at the level of the inflow tracts. (a) B-mode image; (b) power
Doppler image confirming flow at the level of the VSD. LV, left ventricle; RV, right ventricle.
Sunday, July 28, 13

80. Nasal Bone
Sunday, July 28, 13

81. note THREE distinct lines:
Sunday, July 28, 13

82. note THREE distinct lines:
Sunday, July 28, 13

83. The Nasal Bone Is Absent In:
0
18
35
53
70 65.00
50.00
30.00
2.00
Tri 21 Tri 18 Tri 13 Normal
Sunday, July 28, 13

84. 0
15.00
30.00
45.00
60.00
18.00 19.00
52.00 52.00
45-54 55-64 65-74 75-84
Absent Nasal Bone and CRL
Likelihood Ratio for DS
Cicero S et al US Ob&Gyn,
2004, 23
Sunday, July 28, 13

85. In
chromosomal
normal
fetuses
the
incidence
of
absent
nasal
bone
is
less
than
1%
in
Caucasian
populations
and
about
10%
in
Afro-­‐Caribbean.
31.00
9.00
14.00 15.00
Caucasian Asian
Ethnicity of Mother Cicero et al US OB and Gyn 2004
Liklihood Ratios For Down Syndrome -
Absent Nasal Bone
Sunday, July 28, 13

86. For
a
false
positive
rate
of
5%,
screening
by
a
combination
of
sonography
for
fetal
NT
and
nasal
bone
and
maternal
serum
free
b-­‐hCG
and
PAPP-­‐A
can
potentially
identify
more
than
95%
of
trisomy
21
pregnancies.
The
Nasal
Bone
Sunday, July 28, 13

87. DV Blood
Flow
Sunday, July 28, 13

88. In
more
than
5,000
pregnancies,
including
280
fetuses
with
trisomy
21:
0
20
40
60
80
DV Nomral
5
80
Abnormal
DV
flow
in
about
80%
of
trisomy
21
fetuses
and
in
about
5%
of
chromosomally
normal
fetuses
(Nicolaides
2004)
Sunday, July 28, 13

89. Sunday, July 28, 13

90. Tricuspid
Rugurge
Sunday, July 28, 13

91. Tricuspid regurgitation in
screening for trisomies
Tricuspid regurgitation in screening for
trisomies 21, 18 and 13 and Turner
syndrome at 11 + 0 to 13 + 6 weeks of
gestation
K. O. KAGAN*†, C. VALENCIA*, P. LIVANOS*, D. WRIGHT‡ and K. H.
NICOLAIDES
Ultrasound Obstet Gynecol 2009; 33: 18–22, 2008
Sunday, July 28, 13

92. 0
15
30
45
60
0.9
55.7
33.3
30
37
Normal Tr1 21 Tri 18 Tri 13 Turner
Percentage of Tricuspid regurgitation among
normal and abnormal
Sunday, July 28, 13

93. 0
10
20
30
40
50
60
70
80
90
100
91
100 100 100
T21 T18 Tris 13 Turner S
Detection rates at 3% FPR using screening by
maternal age, fetal NT, FHR, free β-hCG and PAPP-A
with and without assessment of tricuspid blood flow
Total
96%
+ 6%
Sunday, July 28, 13

94. Detection rates at given FPR levels using screening by
maternal age, fetal NT, FHR, free β-hCG and PAPP-A with
andwithoutassessmentoftricuspidbloodflow.
Total
92%
+ 12%
Total
95%
Total
96%
Total
96%
Total
96%
+ 11% + 5% + 3% + 2%
Sunday, July 28, 13

95. 0
10
20
30
40
50
60
70
80
90
100
FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0
Detection rates at given FPR levels using screening by
maternal age, fetal NT, FHR, free β-hCG and PAPP-A with
andwithoutassessmentoftricuspidbloodflow.
Total
92%
+ 12%
Total
95%
Total
96%
Total
96%
Total
96%
+ 11% + 5% + 3% + 2%
Sunday, July 28, 13

96. 0
10
20
30
40
50
60
70
80
90
100
80.00
FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0
Detection rates at given FPR levels using screening by
maternal age, fetal NT, FHR, free β-hCG and PAPP-A with
andwithoutassessmentoftricuspidbloodflow.
Total
92%
+ 12%
Total
95%
Total
96%
Total
96%
Total
96%
+ 11% + 5% + 3% + 2%
Sunday, July 28, 13

97. 0
10
20
30
40
50
60
70
80
90
100
80.00
86.00
FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0
Detection rates at given FPR levels using screening by
maternal age, fetal NT, FHR, free β-hCG and PAPP-A with
andwithoutassessmentoftricuspidbloodflow.
Total
92%
+ 12%
Total
95%
Total
96%
Total
96%
Total
96%
+ 11% + 5% + 3% + 2%
Sunday, July 28, 13

98. 0
10
20
30
40
50
60
70
80
90
100
80.00
86.00
91.00
FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0
Detection rates at given FPR levels using screening by
maternal age, fetal NT, FHR, free β-hCG and PAPP-A with
andwithoutassessmentoftricuspidbloodflow.
Total
92%
+ 12%
Total
95%
Total
96%
Total
96%
Total
96%
+ 11% + 5% + 3% + 2%
Sunday, July 28, 13

99. 0
10
20
30
40
50
60
70
80
90
100
80.00
86.00
91.00 93.00
FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0
Detection rates at given FPR levels using screening by
maternal age, fetal NT, FHR, free β-hCG and PAPP-A with
andwithoutassessmentoftricuspidbloodflow.
Total
92%
+ 12%
Total
95%
Total
96%
Total
96%
Total
96%
+ 11% + 5% + 3% + 2%
Sunday, July 28, 13

100. 0
10
20
30
40
50
60
70
80
90
100
80.00
86.00
91.00 93.00 94.00
FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0
Detection rates at given FPR levels using screening by
maternal age, fetal NT, FHR, free β-hCG and PAPP-A with
andwithoutassessmentoftricuspidbloodflow.
Total
92%
+ 12%
Total
95%
Total
96%
Total
96%
Total
96%
+ 11% + 5% + 3% + 2%
Sunday, July 28, 13

101. 0
10
20
30
40
50
60
70
80
90
100
80.00
86.00
91.00 93.00 94.00
FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0
Detection rates at given FPR levels using screening by
maternal age, fetal NT, FHR, free β-hCG and PAPP-A with
andwithoutassessmentoftricuspidbloodflow.
Total
92%
+ 12%
Total
95%
Total
96%
Total
96%
Total
96%
+ 11% + 5% + 3% + 2%
Sunday, July 28, 13

102. 0
10
20
30
40
50
60
70
80
90
100
80.00
86.00
91.00 93.00 94.00
FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0
Detection rates at given FPR levels using screening by
maternal age, fetal NT, FHR, free β-hCG and PAPP-A with
andwithoutassessmentoftricuspidbloodflow.
Total
92%
+ 12%
Total
95%
Total
96%
Total
96%
Total
96%
+ 11% + 5% + 3% + 2%
Sunday, July 28, 13

103. 0
10
20
30
40
50
60
70
80
90
100
80.00
86.00
91.00 93.00 94.00
FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0
Detection rates at given FPR levels using screening by
maternal age, fetal NT, FHR, free β-hCG and PAPP-A with
andwithoutassessmentoftricuspidbloodflow.
Total
92%
+ 12%
Total
95%
Total
96%
Total
96%
Total
96%
+ 11% + 5% + 3% + 2%
Sunday, July 28, 13

104. 0
10
20
30
40
50
60
70
80
90
100
80.00
86.00
91.00 93.00 94.00
FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0
Detection rates at given FPR levels using screening by
maternal age, fetal NT, FHR, free β-hCG and PAPP-A with
andwithoutassessmentoftricuspidbloodflow.
Total
92%
+ 12%
Total
95%
Total
96%
Total
96%
Total
96%
+ 11% + 5% + 3% + 2%
Sunday, July 28, 13

105. 0
10
20
30
40
50
60
70
80
90
100
80.00
86.00
91.00 93.00 94.00
FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0
Detection rates at given FPR levels using screening by
maternal age, fetal NT, FHR, free β-hCG and PAPP-A with
andwithoutassessmentoftricuspidbloodflow.
Total
92%
+ 12%
Total
95%
Total
96%
Total
96%
Total
96%
+ 11% + 5% + 3% + 2%
Sunday, July 28, 13

106. Nasal Bone
Tricuspid Regurgitation
Ductus Venousus
Figure 3 Four-chamber view illustrating an endocardial cushion
defect in which a ventricular (VSD) and atrial (ASD) septal defect
are present. LA, left atrium; LV, left ventricle; RA, right atrium;
RV, right ventricle.
SUGGESTED USE OF FETAL
ECHOCARDIOGRAPHY AS PART OF THE
GENETIC SONOGRAM GIVEN CURRENT
SCREENING TECHNOLOGIES
At present, common screening tests for trisomy 21 may
include any of the following: (1) first-trimester combined
NT and serum screening, (2) first-trimester combined
NT and serum screening plus second-trimester QUAD
screening, (3) first-trimester serum and second-trimester
Genetic sonography as an adjunct to first-trimester NT
and serum and/or second-trimester serum screening
When genetic sonography was first introduced in the
early 1990s it was an option for screening for trisomy
21 in women less than 35 years of age for two reasons:
(1) the detection rate was similar to or higher than that
using MSAFP screening, and (2) the ultrasound exam only
required measurements of the biparietal diameter, femur
length and nuchal skin fold (Table 1). However, as more
analytes were added, second-trimester maternal serum
(triple and QUAD) screening increased the detection
rate for trisomy 21, was easier to use, and did not
require the specialized ultrasound skills needed to keep
the genetic sonogram comparable in terms of detection
rates (Table 2).
Investigators have reported the use of genetic sono-
graphy as an adjunct to other screening protocols.
In 2001, Roberto Romero and I11
reported offer-
ing genetic sonography to women considered to be
at moderate risk (1 : 190–1 : 1000) for trisomy 21
Figure 4 Four-chamber view illustrating a ventricular septal defect (VSD) at the level of the inflow tracts. (a) B-mode image; (b) power
Doppler image confirming flow at the level of the VSD. LV, left ventricle; RV, right ventricle.
Value of Adding
Multiple Markers
Sunday, July 28, 13

107. Benefit of Multiple Ultrasound
Markers
NT
+
Serum
NT+Serum
+
Nasal Bone
+
Heart
+
DV
Tri 21 Tri 81
1st Trimester
75%
96%
69%
90%
NT
+
Serum
NT+Serum
+
NasalBone
+
Heart
+
DV
Sunday, July 28, 13

108. 2ND TRIMESTER
SCREENING
“Genetic Sonography”
Sunday, July 28, 13

109. Is based on the application of the
likelihood ratios obtained from
multiple independent ultrasound
markers markers in adjusting a
priori risk to determine a patient’s
specific risk of carrying a fetus with
DS
Genetic
Ultrasound
Sunday, July 28, 13

110. Likelihood ratios (LR): for each marker are calculated
by dividing the sensitivity of a particular marker by its
false- positive rate.
LR < 1
LR > 1-5
LR > 5-10
LR > 10
Small increase
Moderate increase
Large Increase
Decrease Probability
Sunday, July 28, 13

111. The relative risk “RR”: is the probability
of a fetus having trisomy 21 when
compared with a fetus without this
condition.
e.g. The presence of an ultrasound marker
with a RR of 4 suggests a four-fold
increasefromthepreviousrisk.
Sunday, July 28, 13

112. Example:
A pericardial effusion with a relative risk 10.02.
APatientWith Prior Risk ForTrisomy 21 Is 1 In 270
Sunday, July 28, 13

113. Calculation of Risk:
1. Divide 1/(270–1) = 0.0037
2. Multiply the prior risk (0.0037) by (10.02)
Calculation = 0.0037 × 10.02 = 0.037
3. Divide 1/0.037 = 28
Example:
A pericardial effusion with a relative risk 10.02.
APatientWith Prior Risk ForTrisomy 21 Is 1 In 270
The New Risk For Trisomy 21 is 1 in 28
Sunday, July 28, 13

114. Example:
Normal ultrasound examination study in which
none of the ultrasound markers is present
Patient with Prior risk for trisomy 21 is 1 in 100
The RR following a normal study is 0.11
Sunday, July 28, 13

115. Calculation of Risk:
1.Divide 1/(100–1) = 0.01
2.Multiply the prior risk (0.01) by the RR for
both findings, 0.11
3.Calculation = 0.01 × 0.11 = 0.0011
4.Divide 1/00.11 = 900
Example:
Normal ultrasound examination study in which
none of the ultrasound markers is present
Patient with Prior risk for trisomy 21 is 1 in 100
The RR following a normal study is 0.11
The New Risk For Trisomy 21 is 1 in 900
Sunday, July 28, 13

116. Head
Heart
Abdomen
Sunday, July 28, 13

117. Head
Heart
Abdomen
➡CP
➡CNS
(other
than
CP)
➡NSF
Sunday, July 28, 13

118. Head
Heart
Abdomen
➡CP
➡CNS
(other
than
CP)
➡NSF
➡VSD
➡Rt
to
Lt.
Disp
➡Outflow
tract
abnormalities*
➡Pericardial
Effusion
➡Tricuspid
or
mitral
regurgitation
Sunday, July 28, 13

119. Head
Heart
Abdomen
➡CP
➡CNS
(other
than
CP)
➡NSF
➡VSD
➡Rt
to
Lt.
Disp
➡Outflow
tract
abnormalities*
➡Pericardial
Effusion
➡Tricuspid
or
mitral
regurgitation
➡Hyperechoic
Bowel
➡Pyelectasis
Sunday, July 28, 13

120. CNS abnormalities
IncreasedNFS
VSD
R-LDisproportion
PericaridalEffusion
TricuspidRegurg
HyperechoicBowel
Pyelectasis
Head Structural
heartdefects
Functional
heartdefects Abdomen
(RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with
trisomy 215 (with sensitivity 91% and false-positive rate 14%)
DeVore GR. 2000
Sunday, July 28, 13

121. 0
20.00
40.00
60.00
80.00
71.31
24.85
CNS abnormalities
IncreasedNFS
VSD
R-LDisproportion
PericaridalEffusion
TricuspidRegurg
HyperechoicBowel
Pyelectasis
Head Structural
heartdefects
Functional
heartdefects Abdomen
(RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with
trisomy 215 (with sensitivity 91% and false-positive rate 14%)
DeVore GR. 2000
Sunday, July 28, 13

122. 0
20.00
40.00
60.00
80.00
71.31
24.85
CNS abnormalities
IncreasedNFS
VSD
R-LDisproportion
PericaridalEffusion
TricuspidRegurg
HyperechoicBowel
Pyelectasis
88.26
12.54
Head Structural
heartdefects
Functional
heartdefects Abdomen
(RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with
trisomy 215 (with sensitivity 91% and false-positive rate 14%)
DeVore GR. 2000
Sunday, July 28, 13

123. 0
20.00
40.00
60.00
80.00
71.31
24.85
CNS abnormalities
IncreasedNFS
VSD
R-LDisproportion
PericaridalEffusion
TricuspidRegurg
HyperechoicBowel
Pyelectasis
88.26
12.54
5.89
10.02
Head Structural
heartdefects
Functional
heartdefects Abdomen
(RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with
trisomy 215 (with sensitivity 91% and false-positive rate 14%)
DeVore GR. 2000
Sunday, July 28, 13

124. 0
20.00
40.00
60.00
80.00
71.31
24.85
CNS abnormalities
IncreasedNFS
VSD
R-LDisproportion
PericaridalEffusion
TricuspidRegurg
HyperechoicBowel
Pyelectasis
88.26
12.54
5.89
10.02
4.57
5.65
Head Structural
heartdefects
Functional
heartdefects Abdomen
(RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with
trisomy 215 (with sensitivity 91% and false-positive rate 14%)
DeVore GR. 2000
Sunday, July 28, 13

125. 0
20.00
40.00
60.00
80.00
71.31
24.85
CNS abnormalities
IncreasedNFS
VSD
R-LDisproportion
PericaridalEffusion
TricuspidRegurg
HyperechoicBowel
Pyelectasis
88.26
12.54
5.89
10.02
4.57
5.65
Head Structural
heartdefects
Functional
heartdefects Abdomen
(RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with
trisomy 215 (with sensitivity 91% and false-positive rate 14%)
DeVore GR. 2000
Sunday, July 28, 13

126. 0
20.00
40.00
60.00
80.00
71.31
24.85
CNS abnormalities
IncreasedNFS
VSD
R-LDisproportion
PericaridalEffusion
TricuspidRegurg
HyperechoicBowel
Pyelectasis
88.26
12.54
5.89
10.02
4.57
5.65
Head Structural
heartdefects
Functional
heartdefects Abdomen
(RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with
trisomy 215 (with sensitivity 91% and false-positive rate 14%)
DeVore GR. 2000
Sunday, July 28, 13

127. 0
20.00
40.00
60.00
80.00
71.31
24.85
CNS abnormalities
IncreasedNFS
VSD
R-LDisproportion
PericaridalEffusion
TricuspidRegurg
HyperechoicBowel
Pyelectasis
88.26
12.54
5.89
10.02
4.57
5.65
Head Structural
heartdefects
Functional
heartdefects Abdomen
(RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with
trisomy 215 (with sensitivity 91% and false-positive rate 14%)
DeVore GR. 2000
Sunday, July 28, 13

128. 0
25
50
75
100
60
91
Without Color Doppler
With Color Doppler
The use of fetal echocardiography when performing the genetic
sonogram: 98% detection rate for trisomy 21 in high-risk women
Devore, 2006
Sunday, July 28, 13

129. Meta-analysis of second-trimester markers for trisomy
21
Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, London, UK
(2012)
The aim: to examine the screening
p e r f o r m a n c e o f s e c o n d - t r i m e s t e r
sonographic markers for the detection of
trisomy 21.
Sunday, July 28, 13

130. 0.460.710.740.800.920.900.800.940.80
23.26
21.48
4.80
3.72
7.77
10.82
19.18
25.78
5.80
ICF
Ventriculomegaly
IncreasedNF
HyperechogenicB.
Mildhydronephrosis
ShortFemur
ShortHumerus
ARSA
AbsentNasalBone
Sunday, July 28, 13

131. 0.460.710.740.800.920.900.800.940.80
23.26
21.48
4.80
3.72
7.77
10.82
19.18
25.78
5.80
ICF
Ventriculomegaly
IncreasedNF
HyperechogenicB.
Mildhydronephrosis
ShortFemur
ShortHumerus
ARSA
AbsentNasalBone
✤Ventriculomegaly, NF And ARSA Increases The Risk By 3-4 Fold
✤Hypoplastic Nasal Bone Increases The Risk By 6-7 Fold
Sunday, July 28, 13

132. ✤In The Absence Of All Major Defects And Markers There Is
A7.7-fold Reduction In Risk For Trisomy 21.
✤The Detection Of Any One Of The Markers Should
Stimulate The Sonographer To Look For All Other Markers
Or Defects.
✤The Post- Test Odds For Trisomy 21 Is Derived By
Multiplying The Pre-test Odds With The Positive LR For
Each Detected Marker And The Negative LR For Each
Marker Demonstrated To BeAbsent.
✤In The Case Of Most Isolated Markers, Including
Intracardiac Echogenic Focus, Echogenic Bowel, Mild
Hydronephrosis And Short Femur, There Is Only A Small
Effect On Modifying The Pre-test Odds.
Sunday, July 28, 13

133. 0
0.25
0.50
0.75
1.00
LR
0.37
LR
0.10
The LR for trisomy 21 in the absence of sonographic markers
LR 0.37 RR 0.11
Nicoloides et al Devore
Sunday, July 28, 13

134. Genetic sonography as an adjunct to first-trimester NT and
serum and/or second-trimester serum screening
0
25.00
50.00
75.00
100.00
90.00
98.00
90.00
81.00
93.00
81.00
CombinedTest 1st &2nd
Trim
Integrated
QUAD
Aagaard-Tillery KM, et al First and SecondTrimester Evaluation of Risk Research Consortium. Role of second-
trimestergeneticsonographyafterDownsyndromescreening.ObstetGynecol2009;114
Sunday, July 28, 13

135. NT plus Serum NT, Serum, NB,TR,
DV, Heart
83% 96%
1st Trimester Options
1st Trimester Options
Sunday, July 28, 13

136. Serum
Integrated
Fully
Integrated
80% 85%
2nd Trimester Detection
Rate
2nd Trimester
Options
QUAD
90%
QUAD +
Genetic U/S
2nd Trimester
Detection Rate
99%
2nd + 1st Trimester Options
Sunday, July 28, 13

137. Putting It
Together
Sunday, July 28, 13

138. Initial Testing
Maternal Age
Serum Screening
Nuchal Translucency
+
+
Sunday, July 28, 13

139. > 90% Detection Rate False Positive Rate 2%
Estimated Risk For Trisomy 21
Sunday, July 28, 13

140. High-Risk
(>1 in 100)
(2% of Polulation)
> 90% Detection Rate False Positive Rate 2%
Estimated Risk For Trisomy 21
Sunday, July 28, 13

141. High-Risk
(>1 in 100)
(2% of Polulation)
CVS
> 90% Detection Rate False Positive Rate 2%
Estimated Risk For Trisomy 21
Sunday, July 28, 13

142. High-Risk
(>1 in 100)
(2% of Polulation)
CVS
Low-Risk
(>1in1001in10,100)
(82%ofPolulation)
> 90% Detection Rate False Positive Rate 2%
Estimated Risk For Trisomy 21
Sunday, July 28, 13

143. High-Risk
(>1 in 100)
(2% of Polulation)
CVS
Low-Risk
(>1in1001in10,100)
(82%ofPolulation)
No Further
Testing
> 90% Detection Rate False Positive Rate 2%
Estimated Risk For Trisomy 21
Sunday, July 28, 13

144. High-Risk
(>1 in 100)
(2% of Polulation)
CVS
Low-Risk
(>1in1001in10,100)
(82%ofPolulation)
No Further
Testing
Intermediate-Risk
(1 in 101 to 1 in 1,000)
(16% of Polulation)
> 90% Detection Rate False Positive Rate 2%
Estimated Risk For Trisomy 21
Sunday, July 28, 13

145. High-Risk
(>1 in 100)
(2% of Polulation)
CVS
Low-Risk
(>1in1001in10,100)
(82%ofPolulation)
No Further
Testing
Intermediate-Risk
(1 in 101 to 1 in 1,000)
(16% of Polulation)
> 90% Detection Rate False Positive Rate 2%
Estimated Risk For Trisomy 21
UltrasoundExaminationfor
•AbsentNasalBone
•AbnormalDuctusVenosusFlow
•TricuscupidRrgurgitation
Sunday, July 28, 13

146. High-Risk
(>1 in 100)
(2% of Polulation)
CVS
Low-Risk
(>1in1001in10,100)
(82%ofPolulation)
No Further
Testing
Intermediate-Risk
(1 in 101 to 1 in 1,000)
(16% of Polulation)
> 90% Detection Rate False Positive Rate 2%
Estimated Risk For Trisomy 21
UltrasoundExaminationfor
•AbsentNasalBone
•AbnormalDuctusVenosusFlow
•TricuscupidRrgurgitation
Positive
Sunday, July 28, 13

147. High-Risk
(>1 in 100)
(2% of Polulation)
CVS
Low-Risk
(>1in1001in10,100)
(82%ofPolulation)
No Further
Testing
Intermediate-Risk
(1 in 101 to 1 in 1,000)
(16% of Polulation)
> 90% Detection Rate False Positive Rate 2%
Estimated Risk For Trisomy 21
UltrasoundExaminationfor
•AbsentNasalBone
•AbnormalDuctusVenosusFlow
•TricuscupidRrgurgitation
Positive Negative
Sunday, July 28, 13

148. High-Risk
(>1 in 100)
(2% of Polulation)
CVS
Low-Risk
(>1in1001in10,100)
(82%ofPolulation)
No Further
Testing
Intermediate-Risk
(1 in 101 to 1 in 1,000)
(16% of Polulation)
> 90% Detection Rate False Positive Rate 2%
Estimated Risk For Trisomy 21
UltrasoundExaminationfor
•AbsentNasalBone
•AbnormalDuctusVenosusFlow
•TricuscupidRrgurgitation
Positive Negative
If This is Not
Available
Sunday, July 28, 13

149. High-Risk
(>1 in 100)
(2% of Polulation)
CVS
Low-Risk
(>1in1001in10,100)
(82%ofPolulation)
No Further
Testing
Intermediate-Risk
(1 in 101 to 1 in 1,000)
(16% of Polulation)
> 90% Detection Rate False Positive Rate 2%
Estimated Risk For Trisomy 21
UltrasoundExaminationfor
•AbsentNasalBone
•AbnormalDuctusVenosusFlow
•TricuscupidRrgurgitation
Positive Negative
If This is Not
Available
Genetic Sonography
Sunday, July 28, 13

150. Examination of fetal cells from
maternal peripheral blood:
Cell-free fetal DNA in maternal
plasma:
Non-­‐invasive
diagnosis
Sunday, July 28, 13

151. Examination of fetal cells from
maternal peripheral blood:
Cell-free fetal DNA in maternal
plasma “cffDNA”:
Non-­‐invasive
diagnosis
Sunday, July 28, 13

152. NIPT
Non Invasive Prenatal Testing
Screening or Diagnosis
Sunday, July 28, 13

153. It is now established that trisomy 21 can be detected
reliably from 10 weeks’ gestation in high-risk
singleton pregnancies with superior sensitivity (>
99%) and specificity (false-positive rate < 1%)
compared with conventional screening methods.
Trisomy 18 and 13 are also detectable, but test
accuracy is less consistent than that for trisomy 21.
Sunday, July 28, 13

154. Clinical validity:
Theclinicalutility:
Sunday, July 28, 13

155. The ability of a test to predict the risk of an outcome and to
categorize patients with different outcomes into separate risk
classes.
Clinical validity:
Theclinicalutility:
Sunday, July 28, 13

156. The ability of a test to predict the risk of an outcome and to
categorize patients with different outcomes into separate risk
classes.
Clinical validity:
Theclinicalutility:
The ability of a test to improve health outcomes for patients.
Specifically, the test results must change clinical decision-
making,andthesechangesshouldbebeneficialtopatients.
Sunday, July 28, 13

157. The ability of a test to predict the risk of an outcome and to
categorize patients with different outcomes into separate risk
classes.
Clinical validity:
Theclinicalutility:
The ability of a test to improve health outcomes for patients.
Specifically, the test results must change clinical decision-
making,andthesechangesshouldbebeneficialtopatients.
There are currently no studies on the impact of DNA- based
NIPTon patient management or outcome.
Sunday, July 28, 13

158. Current Screening and/or
ultrasound
High risk for aneuploidy
Pretest counseling
Invasive diagnosis
Genetic Counseling
TOP •Continue Pregnancy
•Prepare for affected infant
•Deliver at hospital with
special newborn services
Serum screening and/or
ultrasound examination
Invasive cytogenetic diagnosis
Trisomy 21
Genetic
counseling
TOP •Continue pregnancy
•Prepare for
affectedt infavnct
•Deliver at hospital
with special
newborn servcie
Treat Fetus
Sequencing of Cell
Free DNA
Current Future
And/Or
Sunday, July 28, 13

159. From prenatal genomic diagnosis to fetal
personalized medicine: progress and challenges
Diana W Bianchi
Nature Medicine 18, 1041–1051 (2012) doi:10.1038/nm.2829
Published online 06 July 2012
Thus far, the focus of personalized medicine has been the prevention and treatment of
conditions that affect adults. Although advances in genetic technology have been
applied more frequently to prenatal diagnosis than to fetal treatment, genetic and
genomic information is beginning to influence pregnancy management. Recent
developments in sequencing the fetal genome combined with progress in
understanding fetal physiology using gene expression arrays indicate that we could
have the technical capabilities to apply an individualized medicine approach to the
fetus. Here I review recent advances in prenatal genetic diagnostics, the challenges
associated with these new technologies and how the information derived from them
can be used to advance fetal care. Historically, the goal of prenatal
diagnosis has been to provide an informed choice to
prospective parents. We are now at a point where that goal can
and should be expanded to incorporate genetic, genomic and
transcriptomic data to develop new approaches to fetal
treatment.
Sunday, July 28, 13

160. Sunday, July 28, 13

161. Thanks
Sunday, July 28, 13