contemprary strategy for prenatal diagnosis

Contemporary Strategy for

Prenatal Diagnosis

Professor Hassan Nasrat FRCS, FRCOG

The Fetal Medicine Clinic The First Clinic

JUCOG 2013

Sunday, July 28, 13

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

Diagnosis of aneuploidy

Sunday, July 28, 13

“ 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”

2007Sunday, July 28, 13


Screening For aneuploidy

Sunday, July 28, 13


Assessment of patient specific risk for aneuploidy


Sunday, July 28, 13


Non-‐invasive Methods



Sunday, July 28, 13


Non-‐invasive Methods

Invasive Methods



Sunday, July 28, 13

Strategies of Screening For aneuploidy

Sunday, July 28, 13

0 25 50 75 100

95.0090.00

87.0082.00

91.0081.00

75.0087.00

69.00

75.0021.001985-

1990

1991-1995

1996-2010

Maternal Serum AFP

Genetic Ultrasound

Maternal Serum Triple Marker

Genetic UltrasoundFirst Trimester NT

Maternal Serum QUAD markerGenetic 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

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



The sensi(vity and specificity cannot be used to es+mate the probability of the disease in an individual.

Sunday, July 28, 13




Posi(ve and nega(ve predic(ve are dependent on the prevalence of the disease

Sunday, July 28, 13




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

The likelihood ra(o

Indicate by how much a given test result increases or decreases the probability of developing a condition.

Sunday, July 28, 13

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



The risk may increase or decrease based on the presence (or absence) of certain marker (s)

Sunday, July 28, 13



×


The Background“Priori Risk”

Sunday, July 28, 13



×The Likelihood ratio as Calculated from a

given marker



Sunday, July 28, 13




given marker

a new priori Posterior Risk For

the next test



Sunday, July 28, 13




given marker

a new priori Posterior Risk For

the next test

The different tests are

independent



Sunday, July 28, 13

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 RatioAFP 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

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

Screening for Fetal Aneuploidy

Sunday, July 28, 13


Maternal AgePrevious History Tests

Sunday, July 28, 13



Biochemical Tests

Sunday, July 28, 13



Biochemical Tests

Sonography Findings

Sunday, July 28, 13



Sonography Findings

Sunday, July 28, 13



Sunday, July 28, 13

Risk of Aneuploidy based on Maternal Age and Gestational

Week

Sunday, July 28, 13

Sunday, July 28, 13

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 andMaternal Age

Sunday, July 28, 13

Risk of Aneuploidy based on Previous Trisomy

Sunday, July 28, 13

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

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



Sunday, July 28, 13



Biochemical Tests

Sunday, July 28, 13

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

9

Down’s syndrome Unaffected

AFP (MoM) uE3 (MoM)

UnaffectedDown’s syndrome

Nuchal translucency (MoM)

Down’s syndromeUnaffected

Down'ssyndrome

Unaffected

Inhibin-A (MoM)

Down’s syndrome

PAPP-A (MoM)

Unaffected

Unaffected Down’s syndrome

free ß-hCG (MoM)

9


AFP (MoM) uE3 (MoM)




Down'ssyndrome

Unaffected

Inhibin-A (MoM)

Down’s syndrome

PAPP-A (MoM)

Unaffected


free ß-hCG (MoM)

9


AFP (MoM) uE3 (MoM)




Down'ssyndrome

Unaffected

Inhibin-A (MoM)

Down’s syndrome

PAPP-A (MoM)

Unaffected


free ß-hCG (MoM)

9


AFP (MoM) uE3 (MoM)




Down'ssyndrome

Unaffected

Inhibin-A (MoM)

Down’s syndrome

PAPP-A (MoM)

Unaffected


free ß-hCG (MoM)

9


AFP (MoM) uE3 (MoM)




Down'ssyndrome

Unaffected

Inhibin-A (MoM)

Down’s syndrome

PAPP-A (MoM)

Unaffected


free ß-hCG (MoM)

9


AFP (MoM) uE3 (MoM)




Down'ssyndrome

Unaffected

Inhibin-A (MoM)

Down’s syndrome

PAPP-A (MoM)

Unaffected


free ß-hCG (MoM)

Unaffected D Syndrome


D SyndromeUnaffected

Unaffected Unaffected


D Syndrome D Syndrome

Sunday, July 28, 13

✦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

THREE SCREENING OPTIONS

2nd TrimesterQuad

1st TrimesterCombined Test

1st and 2nd TrimesterFully Integrated Test

Serum IntegratedStepwise Sequential Contingent

Sequential Screen

Sunday, July 28, 13



Sunday, July 28, 13

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

COMBINED TEST

1Blood 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

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 TestOverall Detection Rate 85%

MATERNAL AGE

DETECTION RATE OF TRISOMY 21 BASED ON MATERNAL AGE

85%

50%

Sunday, July 28, 13


2nd TrimesterQuad


Sunday, July 28, 13

1...9 10 11 12 13 14 15 16 17 18 19 20......40

15 to 20wks

Blood Draw

Quad TestQuad

AFPhCGUe3Inhibin

Sunday, July 28, 13

QUAD TEST

0

25

50

75

100

80.00

67.00

97.00

80.0085.00

60.00

Tri 21 Tri 18 Anecephaly Spina Bifida Abd W D SLOS

Detection Rate

Sunday, July 28, 13

What Does A Negative Test Miss?

0

10

20

30

40

20

33

3

2015

40

Tri 21 Tri 18 Anecephaly Spina Bifida Abd W D SLOS

Percent of Birth Defects Not Detected

Sunday, July 28, 13


2nd TrimesterQuad


1st and 2nd TrimesterFully Integrated Test

Serum Integrated Sequential Screen Contingent Screen

Sunday, July 28, 13

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

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

AFPhCGUe3InhibinMeasurement of CRL

+

PAPPA-A hCG

11 to 14 wks Nuchal

Translucency

Sunday, July 28, 13

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

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

AFPhCGUe3InhibinMeasurement of CRL

+

PAPPA-A hCG

Sunday, July 28, 13

First-trimester Screening

Screen Positive

CVS

Final Result incorporate 1st and 2nd

results

Screen Negative

CVS

QUAD

Sequential Screen

Sunday, July 28, 13

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

No Additional Test

CVSSunday, July 28, 13

First Trimester

Second Trimester

1st & 2nd Trimester

Sunday, July 28, 13

0

25

50

75

100

First Trimester

Second Trimester

1st & 2nd Trimester

Sunday, July 28, 13

0

25

50

75

10075

First Trimester

Second Trimester

1st & 2nd Trimester

Sunday, July 28, 13

0

25

50

75

10075

85

NT NT+

PAPP-A &

β-hCG

First Trimester

Second Trimester

1st & 2nd Trimester

Sunday, July 28, 13

0

25

50

75

10075

8575

NTAFP+

Ue3 &

β-hCG

NT+

PAPP-A &

β-hCG

First Trimester

Second Trimester

1st & 2nd Trimester

Sunday, July 28, 13

0

25

50

75

10075

8575

NTAFP+

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

0

25

50

75

10075

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

0

25

50

75

10075

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

0

25

50

75

10075

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

0

25

50

75

10075

85

NT NT+

PAPP-A &

β-hCG

85

AFP+

Ue3 &

β-hCG&

Inhibin

“QUAD “

9585

NT+

PAPP-A &

β-hCG

“QUAD”

PAPP-A &

β-hCG What if NT is Not Available?

First Trimester

Second Trimester

1st & 2nd Trimester

“QUAD”

Sunday, July 28, 13

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


90%

50%

Sunday, July 28, 13

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


80%72%

Sunday, July 28, 13

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


MATERNAL AGE


90%

50%

Sunday, July 28, 13

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


MATERNAL AGE


90%

50%

HOW?90+%

Sunday, July 28, 13



Biochemical Tests

Sunday, July 28, 13



Biochemical Tests

Sonography Findings

Sunday, July 28, 13

FIRST TRIMESTER

SECOND TRIMESTER

Sunday, July 28, 13

1ST TRIMESTER SCREENING

Sunday, July 28, 13

Nasal Bone

Tricuspid Regurgitation

Ductus Venousus

Editorial 515

Figure 3 Four-chamber view illustrating an endocardial cushiondefect in which a ventricular (VSD) and atrial (ASD) septal defectare present. LA, left atrium; LV, left ventricle; RA, right atrium;RV, right ventricle.

SUGGESTED USE OF FETALECHOCARDIOGRAPHY AS PART OF THEGENETIC SONOGRAM GIVEN CURRENTSCREENING TECHNOLOGIES

At present, common screening tests for trisomy 21 mayinclude any of the following: (1) first-trimester combinedNT and serum screening, (2) first-trimester combinedNT and serum screening plus second-trimester QUADscreening, (3) first-trimester serum and second-trimester

serum screening, or (4) second-trimester QUAD screen-ing. Because of the technical skills of the sonogra-pher/sonologist required to detect over 90% of trisomy 21fetuses using non-cardiac and cardiac markers (Table 8),genetic sonography should only be used as an adjunctto the above screening protocols or in women who reg-ister for prenatal care after 20 weeks of gestation. Thefollowing two scenarios illustrate when genetic sono-graphy, coupled with fetal echocardiography, should beconsidered.

Genetic sonography as an adjunct to first-trimester NTand serum and/or second-trimester serum screening

When genetic sonography was first introduced in theearly 1990s it was an option for screening for trisomy21 in women less than 35 years of age for two reasons:(1) the detection rate was similar to or higher than thatusing MSAFP screening, and (2) the ultrasound exam onlyrequired measurements of the biparietal diameter, femurlength and nuchal skin fold (Table 1). However, as moreanalytes were added, second-trimester maternal serum(triple and QUAD) screening increased the detectionrate for trisomy 21, was easier to use, and did notrequire the specialized ultrasound skills needed to keepthe genetic sonogram comparable in terms of detectionrates (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 beat 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) powerDoppler image confirming flow at the level of the VSD. LV, left ventricle; RV, right ventricle.

Copyright ! 2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 35: 509–521.

Sunday, July 28, 13

Nasal Bone

Sunday, July 28, 13

note THREE distinct lines:Sunday, July 28, 13

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

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

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

9.0014.00 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

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

DV Blood

FlowSunday, July 28, 13

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

Sunday, July 28, 13

Tricuspid Rugurge

Sunday, July 28, 13

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 gestationK. O. KAGAN*†, C. VALENCIA*, P. LIVANOS*, D. WRIGHT‡ and K. H. NICOLAIDESUltrasound Obstet Gynecol 2009; 33: 18–22, 2008

Sunday, July 28, 13

0

15

30

45

60

0.9

55.7

33.3 3037

Normal Tr1 21 Tri 18 Tri 13 Turner

Percentage of Tricuspid regurgitation among normal and abnormal

Sunday, July 28, 13

0102030405060

7080

90100

91100 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

Detection rates at given FPR levels using screening by maternal age, fetal NT, FHR, free β-hCG and PAPP-A with and without assessment of tricuspid blood flow.

Total 92%

+ 12%

Total 95%

Total 96%

Total 96%

Total 96%

+ 11% + 5% + 3% + 2%

Sunday, July 28, 13

0102030405060

70

80

90

100

FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0


Total 92%

+ 12%

Total 95%

Total 96%

Total 96%

Total 96%

+ 11% + 5% + 3% + 2%

Sunday, July 28, 13

0102030405060

70

80

90

100

80.00



Total 92%

+ 12%

Total 95%

Total 96%

Total 96%

Total 96%

+ 11% + 5% + 3% + 2%

Sunday, July 28, 13

0102030405060

70

80

90

100

80.0086.00



Total 92%

+ 12%

Total 95%

Total 96%

Total 96%

Total 96%

+ 11% + 5% + 3% + 2%

Sunday, July 28, 13

0102030405060

70

80

90

100

80.0086.00 91.00



Total 92%

+ 12%

Total 95%

Total 96%

Total 96%

Total 96%

+ 11% + 5% + 3% + 2%

Sunday, July 28, 13

0102030405060

70

80

90

100

80.0086.00 91.00 93.00



Total 92%

+ 12%

Total 95%

Total 96%

Total 96%

Total 96%

+ 11% + 5% + 3% + 2%

Sunday, July 28, 13

0102030405060

70

80

90

100

80.0086.00 91.00 93.00 94.00



Total 92%

+ 12%

Total 95%

Total 96%

Total 96%

Total 96%

+ 11% + 5% + 3% + 2%

Sunday, July 28, 13

Nasal BoneTricuspid Regurgitation

Ductus Venousus

Editorial 515

Figure 3 Four-chamber view illustrating an endocardial cushiondefect in which a ventricular (VSD) and atrial (ASD) septal defectare present. LA, left atrium; LV, left ventricle; RA, right atrium;RV, right ventricle.

SUGGESTED USE OF FETALECHOCARDIOGRAPHY AS PART OF THEGENETIC SONOGRAM GIVEN CURRENTSCREENING TECHNOLOGIES

At present, common screening tests for trisomy 21 mayinclude any of the following: (1) first-trimester combinedNT and serum screening, (2) first-trimester combinedNT and serum screening plus second-trimester QUADscreening, (3) first-trimester serum and second-trimester

serum screening, or (4) second-trimester QUAD screen-ing. Because of the technical skills of the sonogra-pher/sonologist required to detect over 90% of trisomy 21fetuses using non-cardiac and cardiac markers (Table 8),genetic sonography should only be used as an adjunctto the above screening protocols or in women who reg-ister for prenatal care after 20 weeks of gestation. Thefollowing two scenarios illustrate when genetic sono-graphy, coupled with fetal echocardiography, should beconsidered.

Genetic sonography as an adjunct to first-trimester NTand serum and/or second-trimester serum screening

When genetic sonography was first introduced in theearly 1990s it was an option for screening for trisomy21 in women less than 35 years of age for two reasons:(1) the detection rate was similar to or higher than thatusing MSAFP screening, and (2) the ultrasound exam onlyrequired measurements of the biparietal diameter, femurlength and nuchal skin fold (Table 1). However, as moreanalytes were added, second-trimester maternal serum(triple and QUAD) screening increased the detectionrate for trisomy 21, was easier to use, and did notrequire the specialized ultrasound skills needed to keepthe genetic sonogram comparable in terms of detectionrates (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 beat 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) powerDoppler image confirming flow at the level of the VSD. LV, left ventricle; RV, right ventricle.

Copyright ! 2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 35: 509–521.

Value of Adding Multiple Markers

Sunday, July 28, 13

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 +

Nasal Bone +

Heart +

DV

Sunday, July 28, 13

2ND TRIMESTER SCREENING

“Genetic Sonography”

Sunday, July 28, 13

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

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

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 increase from the previous risk.

Sunday, July 28, 13

Example: A pericardial effusion with a relative risk 10.02.

A Patient With Prior Risk For Trisomy 21 Is 1 In 270

Sunday, July 28, 13

Calculation of Risk:1. Divide 1/(270–1) = 0.00372. Multiply the prior risk (0.0037) by (10.02)

Calculation = 0.0037 × 10.02 = 0.0373. Divide 1/0.037 = 28

Example: A pericardial effusion with a relative risk 10.02.

A Patient With Prior Risk For Trisomy 21 Is 1 In 270

The New Risk For Trisomy 21 is 1 in 28Sunday, July 28, 13

Example: Normal ultrasound examination study in which none of the ultrasound markers is present

Patient with Prior risk for trisomy 21 is 1 in 100The RR following a normal study is 0.11

Sunday, July 28, 13

Calculation of Risk:1.Divide 1/(100–1) = 0.012.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 100The RR following a normal study is 0.11

The New Risk For Trisomy 21 is 1 in 900Sunday, July 28, 13

Head

Heart

Abdomen

Sunday, July 28, 13

Head

Heart

Abdomen

➡CP

➡CNS (other than CP)

➡NSF

Sunday, July 28, 13

Head

Heart

Abdomen

➡CP


➡NSF

➡VSD

➡Rt to Lt. Disp

➡Outflow tract abnormalities*

➡Pericardial Effusion

➡Tricuspid or mitral regurgitation

Sunday, July 28, 13

Head

Heart

Abdomen

➡CP


➡NSF

➡VSD

➡Rt to Lt. Disp

➡Outflow tract abnormalities*

➡Pericardial Effusion

➡Tricuspid or mitral regurgitation

➡Hyperechoic Bowel

➡Pyelectasis Sunday, July 28, 13

CNS abno

rmalities

Increas

ed NFS VSD

R-L Dispr

oportio

n

Pericar

idal Effu

sion

Tricusp

id Regu

rg

Hyperec

hoic B

owel

Pyelect

asis

Head Structural heart defects

Functional heart defects 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. 2000Sunday, July 28, 13

0

20.00

40.00

60.00

80.0071.31

24.85

CNS abno

rmalities

Increas

ed NFS VSD

R-L Dispr

oportio

n

Pericar

idal Effu

sion

Tricusp

id Regu

rg

Hyperec

hoic B

owel

Pyelect

asis





0

20.00

40.00

60.00

80.0071.31

24.85

CNS abno

rmalities

Increas

ed NFS VSD

R-L Dispr

oportio

n

Pericar

idal Effu

sion

Tricusp

id Regu

rg

Hyperec

hoic B

owel

Pyelect

asis

88.26

12.54





0

20.00

40.00

60.00

80.0071.31

24.85

CNS abno

rmalities

Increas

ed NFS VSD

R-L Dispr

oportio

n

Pericar

idal Effu

sion

Tricusp

id Regu

rg

Hyperec

hoic B

owel

Pyelect

asis

88.26

12.54

5.89

10.02





0

20.00

40.00

60.00

80.0071.31

24.85

CNS abno

rmalities

Increas

ed NFS VSD

R-L Dispr

oportio

n

Pericar

idal Effu

sion

Tricusp

id Regu

rg

Hyperec

hoic B

owel

Pyelect

asis

88.26

12.54

5.89

10.02

4.57

5.65





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 womenDevore, 2006

Sunday, July 28, 13

Meta-analysis of second-trimester markers for trisomy 21Harris 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

0.460.710.740.800.920.900.800.940.80

23.2621.48

4.803.72

7.77

10.82

19.18

25.78

5.80

ICF

Ventriculomegal

y

Increase

d NF

Hyperechogenic B

.

Mild hydronephrosis

Short Femur

Short Humerus

ARSA

Absent Nasa

l Bone

Sunday, July 28, 13

0.460.710.740.800.920.900.800.940.80

23.2621.48

4.803.72

7.77

10.82

19.18

25.78

5.80

ICF

Ventriculomegal

y

Increase

d NF

Hyperechogenic B

.

Mild hydronephrosis

Short Femur

Short Humerus

ARSA

Absent Nasa

l Bone

✤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

✤In The Absence Of All Major Defects And Markers There Is A 7.7-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 Be Absent.

✤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

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 markersLR 0.37 RR 0.11

Nicoloides et al DevoreSunday, July 28, 13

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

90.0098.00

90.00

81.0093.00

81.00

Combined Test 1st &2nd Trim

IntegratedQUAD

Aagaard-Tillery KM, et al First and Second Trimester Evaluation of Risk Research Consortium. Role of second-trimester genetic sonography after Down syndrome screening. Obstet Gynecol 2009; 114

Sunday, July 28, 13

NT plus Serum NT, Serum, NB, TR, DV, Heart

83% 96%

1st Trimester Options1st Trimester Options

Sunday, July 28, 13

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

Putting It Together

Sunday, July 28, 13

Initial Testing

Maternal Age

Serum Screening

Nuchal Translucency

+

+

Sunday, July 28, 13

> 90% Detection Rate False Positive Rate 2%

Estimated Risk For Trisomy 21

Sunday, July 28, 13

High-Risk(>1 in 100)

(2% of Polulation)



Sunday, July 28, 13


(2% of Polulation)

CVS



Sunday, July 28, 13


(2% of Polulation)

CVS

Low-Risk(>1 in 1001 in 10,100)

(82% of Polulation)



Sunday, July 28, 13


(2% of Polulation)

CVS

Low-Risk(>1 in 1001 in 10,100)

(82% of Polulation)

No Further Testing



Sunday, July 28, 13


(2% of Polulation)

CVS

Low-Risk(>1 in 1001 in 10,100)

(82% of Polulation)

No Further Testing

Intermediate-Risk(1 in 101 to 1 in 1,000)

(16% of Polulation)



Sunday, July 28, 13


(2% of Polulation)

CVS

Low-Risk(>1 in 1001 in 10,100)

(82% of Polulation)

No Further Testing


(16% of Polulation)



Ultrasound Examination for•Absent Nasal Bone•Abnormal Ductus Venosus Flow•Tricuscupid Rrgurgitation

Sunday, July 28, 13


(2% of Polulation)

CVS

Low-Risk(>1 in 1001 in 10,100)

(82% of Polulation)

No Further Testing


(16% of Polulation)




Positive

Sunday, July 28, 13


(2% of Polulation)

CVS

Low-Risk(>1 in 1001 in 10,100)

(82% of Polulation)

No Further Testing


(16% of Polulation)




Positive Negative

Sunday, July 28, 13


(2% of Polulation)

CVS

Low-Risk(>1 in 1001 in 10,100)

(82% of Polulation)

No Further Testing


(16% of Polulation)




Positive Negative

If This is Not Available

Sunday, July 28, 13


(2% of Polulation)

CVS

Low-Risk(>1 in 1001 in 10,100)

(82% of Polulation)

No Further Testing


(16% of Polulation)




Positive Negative

If This is Not Available

Genetic SonographySunday, July 28, 13

Examination of fetal cells from maternal peripheral blood:

Cell-free fetal DNA in maternal plasma:

Non-‐invasive diagnosis

Sunday, July 28, 13

Examination of fetal cells from maternal peripheral blood:

Cell-free fetal DNA in maternal plasma “cffDNA”:

Non-‐invasive diagnosis

Sunday, July 28, 13

NIPTNon Invasive Prenatal Testing

Screening or Diagnosis

Sunday, July 28, 13

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

Clinical validity:

The clinical utility:

Sunday, July 28, 13

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:


Sunday, July 28, 13


Clinical validity:


The ability of a test to improve health outcomes for patients. Specifically, the test results must change clinical decision- making, and these changes should be beneficial to patients.

Sunday, July 28, 13


Clinical validity:


The ability of a test to improve health outcomes for patients. Specifically, the test results must change clinical decision- making, and these changes should be beneficial to patients.

There are currently no studies on the impact of DNA- based NIPT on patient management or outcome.

Sunday, July 28, 13

Current Screening and/or ultrasound

High risk for aneuploidyPretest 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

From prenatal genomic diagnosis to fetal personalized medicine: progress and challengesDiana W Bianchi

Nature Medicine 18, 1041–1051 (2012) doi:10.1038/nm.2829Published 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

Sunday, July 28, 13

Thanks

Sunday, July 28, 13

contemprary strategy for prenatal diagnosis

Business

maternal age

selective nt

adjusted risk

negave predicve

afpmom ue3mom hcgmom

patient specific risk

fetal medicine clinic

invasive diagnostic