Developments in Prenatal Diagnosis

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Developments in Prenatal Diagnosis

• Allan J. Fisher, MD
• Director, Maternal-Fetal Medicine
• Atlantic Health System
• New Jersey

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First Trimester Ultrasound

• The New Frontier

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Birth Distribution

• 1984 5 gt 35 years old
• 1994 11
• 2002 22
• But only 25 of the Down syndrome births are born
  to women who are gt 35 years old

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Maternal Age vs. Percent of Aneuploidy
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Maternal Age vs. Percent of Aneuploidy
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A Priori Down Syndrome Risk

• Maternal Age
• 12 wks 16 wks Term
• 25 y/o 1712 1933 11352
• 30 y/o 1471 1617 1895
• 35 y/o 1187 1246 1356
• 40 y/o 151 167 197
• 45 y/o 116 118 123

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A Priori Down Syndrome Risk
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Fetal Loss Rate for Down Syndrome

• 36 from 10 weeks
• 30 from 12 weeks
• 21 from 16 weeks
• T13 T18 (12-40 wks) 80
• 45,X gt 50
• Polyploidy gt 99

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First Trimester Anatomy

• Embryogenesis-period or organ and tissue
  formation
• Physiologic herniation of the intestine
• Rhombencephalon is cystic between 8-10 weeks
  and the 4th ventricle is later
• Membrane fusion at 11-12 weeks

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Abnormal Nuchal Translucency

• Cystic hygroma (75 aneuploidy)
• Nuchal edema
• Aneuploidy (33-75 T21/T18)
• Cardiac defects
• Skeletal dysplasias
• Congenital infections
• Metabolic hematological disorders
• Normal chromosomes - poor prognosis

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Nuchal Translucency Gestational Age

• NT thickness increases with CRL
• Median increases from 1.2mm
  (11 wks) to 1.9mm (14 wks)
• The 99th percentile is 3.5mm throughout
  this range
• The 95th percentile at 14 wks is 2.8mm

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Technique
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Quality

• Midsagittal
• Caliper placement
• Visualize the skin of the neck back
• Image size 100
• Visualize the amnion separately
• Head position should be straight
• Perform at a specific CRL/dates
  (45-84mm/11w4d-14w)

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Caliper Placement

• Measure the translucency.

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Normal Nuchal Translucency
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Abnormal Nuchal Translucency (6.2mm)
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Fetal Hydrops
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Cystic Hygroma (12 weeks)
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What does this all mean?
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Possible Pathophysiology

• Cardiac failure
• Venous congestion
• Abnormal or delayed development of the lymphatic
  system
• Failure of lymphatic drainage
• Fetal anemia
• Congenital infection
• Alteration of collagen composition

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Aneuploidy Rates

• NT Rates
• 2.5-3.4mm 3
• 3.5-4.4mm 19
• 4.5-5.4mm 32
• 5.5-6.4mm 50
• gt 6.5mm 64

2.5 3.5 4.5 5.5
gt 6.5
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Multicenter Screening Study

• N 100,311 (96,127 followed up)
• 326 with T21, 325 with others
• Median gestational age 12 wks
• Median maternal age 31 yrs
• 13.3 gt 37 years old
• Snijders et al, Lancet
  1998351343-6

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Multicenter Screening Study

• NT gt 95th ile in 4.4 of normals 71.8 of T21
• Estimated risk for T21 above 1300 was 8.3 in
  normals and 82.2 in T21
• With a FP rate 5, sensitivity 77 (95CI
  72-82)

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Multicenter Screening Study

• Karyotype NTgt95th gt1300
• T18 74.8 81.5
• T13 71.7 80.4
• 45,X 87.0 88.9
• Triploidy 59.4 62.5
• Other 55.4 79.7
• TOTAL 70.5 77.9

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Other Features of the Aneuploid Fetus

• Early IUGR
• FHR - increased or decreased
• Abnormal ductus venosus Doppler flow
• with increased NT 90.5
  aneuploid 3.1 normals
• Matias et al Ultrasound Obstet
  Gynecol 199812380-4

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Down Syndrome NT Distribution
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Normal Ductus Venosus
s
D
A
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Abnormal Ductus Venosus
A
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Nasal Bone

• Delayed ossification
• Requires technical ability
• Qualitative vs. quantitative

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Nasal Bone- Qualitative

• N701, 11-14 weeks
• Absent in
• 43 of 59 DS fetuses (73) (OR146)
• 3 of 603 normals (0.5)
• 11 of 20 T18 (55)
• 2 of 8 Turner (25)
• May, in combo, increase sensitivity to 85-90 and
  decrease the FPs to 1
• Cicero,S. et al.
  Lancet,2001,173581665-67

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Nasal Bone

• Orlandi et al. 2003
• N1089
• 94 successful ascertainment
• Unaffected absent 10/1000 (1)
• 10/15 DS absent 67
• Used NB, NT, Biochemical markers
• Sensitivity 95, FPR 2.9

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Nasal Bone - Quantitative

• Unpublished data (Krantz)
• N1027, 11-14 weeks
• Measure length of nasal bone
• LR
• Absent 1 unaffected
• 67 DS 67.0
• 0.5-0.8mm 1.4
• gt 0.8mm 0.2

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Normal Karyotype Increased Nuchal Translucency

• Cardiac defects
• Diaphragmatic hernia
• Skeletal dysplasias
• Beckwith-Wiederman
• Body Stalk anomaly
• Metabolic defects
• Meckel Gruber
• Roberts syndrome
• SLO
• SMA (type 1)

• Fetal akinesia
• Fryn syndrome
• Joubert syndrome
• Noonan syndrome
• VACTERL
• Zellweger syndrome
• ECC syndrome
• Jarcho-Levin syndrome
• Exomphalmos
• Hematological disorders

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Cardiac Defects

• NT Prevalence ( /1000)
• lt 95th 0.8
• 95th-3.4mm 5.3
• 3.5-4.4mm 28.9
• 4.5-5.4mm 90.9
• gt 5.5 195.1
• Hyett et al Br Med J 199931881-5

lt95 3.4 4.4 5.4 gt5.5
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Cardiac Defects

• N 398 fetuses with normal karyotype and abnormal
  NT (gt 3.5mm)
• Antenatal post partum echocardiography
• 7.3 (29) had cardiac defects
• 28 of 29 were detected in utero
• Zosmer et al Br J Obstet
  Gyneacol 1999106(8)829-33

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Cardiac Defects

• Tricuspid Regurgitation
• 46 of those with abnormal karyotype
• Most with T21
• 9 with normal karyotype
• 50 with genetic syndromes
• 54 with CHD
• Reverse flow in Ao arch, DA or PA is associated
  with T18

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Dried Blood Sample
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free b / PAPP-A / Down Syndrome
Detection Rate at 5 FPR
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Free b / PAPP-A / NT DS Detection
Rate
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Biochemical Markers

• Free b hCG PAPP-A NT measured
• N5,809 for both
• 50 DS 20 T18
• DS lt 35 y/o 87.5, FP 4.5
• DS gt 35 y/o 92, FP 14.5
• DS overall modeling (FP5) 91
• T18100 detection FP 0.4-1.4
• Krantz et al Obstet
  Gynecol 200096(2)207-13

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Free b / PAPP-A / NT/ NB DS
Detection Rate

• Unpublished data (Krantz)
• Qualitative
• NTBio NTBioNB Remodel
• Sens. 85-90 90-95 98
• FP 5 2.9 5

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Low PAPP-A

• Adverse outcomes
• SAB
• Preeclampsia
• Abruption
• IUGR

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Low PAPP-A

• N1622 with 11.3 adverse outcomes
• lt 0.25MoM
• IUGR RR3.12
• Pre-eclampsia RR6.09
• SAB RR8.76
• Yaron et al Prenat Diag. 2002, 22(9)778-82

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Low PAPP-A

• N8012
• IUGR
• lt1ile OR 5.4 (1.9-3.9)
• lt5ile OR 2.7 (1.9-5.9)
• lt1ile fbhCG OR 2.7 (1.3-5.9)
• PTL
• lt5ile OR 2.3 (1.1-4.7)
• Krantz et al. 2004 AJOG 191(4)1452-8

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Summary
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Anatomy at 13 weeks
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VSD at 12 weeks
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Anhydraminos at 13 weeks
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3D
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Genetic Ultrasound

• 18-22 weeks, use a priori or MS scrn
• Look for DS markers (12)
• Proficiency needed
• Sensitivity Lab dependent
• Sens.80-90
• FP10
• PPV 11 for 1, 34 for 2
• Adjust DS risk

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Which 2nd Trimester Biochem. Test to Use for DS
Assessment???

• Sens. FP
• Triple Scrn 60-70 5-10
• Quad Scrn 60-80 5-10
• f b / MSAFP 80 2.5
• Integrated 85-90 2

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Summary
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Summary

• Ultrasound detection of fetal abnormalities is
  starting earlier
• Proficiency in proper measurement of the NT and
  other structures is very important
• Despite normal chromosomes, fetuses with an
  enlarged NT are still at risk for other
  anomalies/genetic syndromes or problems

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