Sonographic Detection of Aneuploidy

Eric H. Dellinger, MDDirector, Division of Maternal-Fetal Medicine

Greenville Hospital SystemGreenville, South Carolina

Introduction

The Future of Science and Medicine:

Exploring the extremes

http://www.luminous-landscape.com/1photo-pages/b/big-dipper.shtml

Evolution of Ultrasound

Aneuploidy

Benefits of Early Detection

Privacy issues Decreased maternal bonding Safer pregnancy termination Higher detection rate

Nuchal Translucency Clear space in posterior neck Imaged between 11 and 14 weeks or when

CRL is 36 to 84 mm Nuchal thickening is associated with:

Aneuploidy Anomalies Infections Metabolic and hematologic disorders

Incidence of chromosomal defects

Nuchaltranslucency (mm) Total n Chromosomal defects (%)

< 3.4 95,086 0.333.5 - 4.4 568 21.124.5 - 5.4 207 33.335.5 - 6.4 97 50.51> 6.5 166 64.45

Snijders et al. 1998

Trisomy 21 Detection Rate 96,127 patients studied NT and age Median age 31 years 5% screen positive rate 77% of affected fetuses detected

Snijders et al, Lancet 1998; 352: 343.

Other Associations Genetic syndromes:

Cornelia de Lange, Noonan, Smith-Lemli-Opitz, Apert

Anomalies: Cardiac, diaphragmatic hernia

Adverse outcome: Early demise

Targeted scan indicated if euploid

Anomalies with Increased NT Cardiac defects Diaphragmatic hernia Omphalocele Duodenal atresia Esophageal atresia Skeletal dysplasias Lethal congenital arthryogryposis

Smith-Lemli-Optiz syndrome

Megacystis Fryn syndrome Joubert syndrome Meckel-Gruber

syndrome VATER association

NT and CHD In 29,154 chromosomally normal fetuses, 56%

of major abnormalities of the heart and great arteries were found in the subgroup with nuchal translucency above the 95th centile.

Nuchal translucency thickness at 11–14 weeks may constitute the most effective method of screening for cardiac defects.

Hyett JA, et al, Br Med J 1999:318:81–5

NT and Cardiac Defects

NT CHD per 1000

< 2.0 mm 1.92.0 to 2.4 mm 4.82.5 to 3.4 mm 6.0> 3.4 mm 23

Bahado-Singh et al, Am J Obstet Gynecol. 2005 May;192(5):1357-61

NT Technique

Proper CRL is a MSLL

MSLL = maximum straight line length

Enlarge

Caliper Placement

NT Increase at 11 – 14 weeks

NT Interpretation

From 10 - 14 weeks, the 99th percentile remains constant at 3.5 millimeters, independent of gestational age or crown-rump length.

Nicolaides , Semin Perinatol. 2005;29(4):190.

NT measurement in 326 trisomy 21 fetuses

NT thickness and chromosomal abnormalities other than trisomy 21

Adverse Outcome with Increased NT

NT Poor Outcome

3.5 - 4.4 mm 32% 4.5 - 5.4 mm 49% 5.5 - 6.4 mm 67%> 6.5 mm 89%

Ultrasound Obstet Gynecol 2001;18:9-17

Cutoff 3 mm threshold identifies 80% of Downs

5% SPR High risk population

95th percentile is a better threshold NT between 95th and 99th percentile carries 3.7%

risk of aneuploidy

Br J ObGyn 1994; 101:782

Lancet 1998; 352: 343

Pitfalls

Beware NT cannot be obtained in all patients (~6%)

Fetal position Maternal body habitus Time constraints (allot 20 min)

Identify the amnion

Nuchal thickening may decrease over time

Essential for proper NT Magnify the image until the fetal head and

thorax occupy the whole screen. Obtain a mid-sagittal view of the face.

Minor deviations: non-visualization of the tip of the nose and visibility of the zygomatic process of the maxilla.

The fetus should be in a neutral position.

Essential for proper NT Widest part of NT must be measured.

The crossbar of the calliper should be such that it is hardly visible as it merges with the white line of the border, not in the nuchal fluid.

Turn the gain down. This helps avoid placing the calliper on the fuzzy edge of the line which can underestimate the nuchal measurement.

Amnion vs. NT

Nasal Bone

Nasal Bone Conflicting results in European vs. US

studies May reflect the technical difficulty of

imaging Review of over 35,000 nasal bone exams

from 9 studies: Successful study in 94.3% Absent in 65% of Downs (0.8% of normals)

Obstet Gynecol 2007; 110:300

Nasal Bone The optimum time for nasal bone

assessment is at crown rump length of 65 to 74 mm (13 to 13.5 weeks of gestation).

Absent nasal bone earlier in gestation could reflect delayed maturation, rather than actual absence of the structure.

Ville, Am J Obstet Gynecol. 2006;195(1):1.

Cystic Hygroma

Doppler

Umbilical Ductus

Normal Tricuspid Regurgitation

Tricuspid Regurgitation

Anomalies and Aneuploidy

Normal newborns 0.5% aneuploid

Structural anomalies 11% aneuploid

Am J Med Genet 1988;29:289

Type of Defect Matters

Omphalocele with liver 3 of 34 aneuploid

Omphalocele without liver 12 of 14 aneuploid

AJR 1992;158:133; J Ultra Med 1989;8:299

Growth Restriction

Finding Aneuploid

Isolated IUGR 2 %

IUGR + anomaly 20 %

Am J Obstet Gynecol 1993;168:547

Detecting Down Syndrome

Major Malformation 33% of Down fetuses have one or more

major malformations Heart CNS GI Face/neck Hydrops

Ped Clin N Am 1984;31:1331

Cardiovascular 40-50% manifest heart anomalies

Cardiovascular

AV Canal is the Sine Qua NonOf Down Syndrome

Cardiovascular

AV Canal defect 45 percent Ventricular septal defect 35 percent Isolated secundum ASD 8 percent Isolated persistent PDA 7 percent Isolated tetralogy of Fallot 4 percent Other 1 percent

CNS Brachycephaly, frontal hypoplasia,

ventriculomegaly

GI Duodenal atresia 40% risk, “late” finding

Face, Nuchal Fold In 40-50% nuchal fold > 6 mm at 15-20 wks Seen in 0.5% of normals

Nuchal Thickening

Cystic Hygroma

Hydrops Strong association with non-immune

hydrops

Soft Markers Short femur Short humerus EIF Echogenic bowel Pyelectasis

Hypoplastic 5th digit Sandal gap Wide iliac angle Short nasal bone

Short Femur and HumerusExpected FL = -9.3105 + 0.9028 x BPDMeasured/Expected FL ≤ 0.91 is ABNORMAL

53% of Downs 5% of normals

Expected HL = -7.9404 + 0.8492 x BPDMeasured/Expected HL <0.90 is ABNORMAL

48% of Downs 2% of normals

Echogenic Intracardiac Focus

25 - 34% of Downs4% of Normals15 - 30% of Asians

Echogenic Bowel15% of Downs0.6% of Normals3.6% aneuploid2.9% CF

Think intra-amniotic bleeding, CF, infection, transducer

Pyelectasis

21% of Downs 2% of normals> 4.0 mm

SOFT MARKERS NOT ESTABLISHED FOR CLINICAL PRACTICE

Seen in many normals

Predictive value unclear

Good to know

Hypoplastic 5th Digit

Clinodactyly19% Downs3.4% normals

5th/4th ratio of 0.70

Sandal Gap

Seen in 45% of newborns with Downs

Subtle finding on scan

Brachycephaly

Shortening of the frontaloccipital brain length

Smaller frontal lobes

Not an effective screen

Wide Iliac AngleAngle of 90 degrees should be considered the upper limit of normal

Nasal Bone

Nasal Bone

Other Findings Mild ventriculomegaly (10-14 mm) Enlarged cisternal magna (> 10 mm) Small low-set ears Effusions Duodenal bulb

Case Study 31 year old G3 P2 Down Syndrome risk from Quad screen is

1:430 Level II scan reveals:

EIF Short humerus

Should she have an amniocentesis?

Are You Confused?

Likelihood Ratio (LR)

LR = sensitivity / false-positive rate = + test with disease / + test no disease An LR > 1 suggests a positive association with a particular finding

An LR of 10 or more suggests a strong association with a particular finding

Calculated LRs of Sonographic Findings for Fetal Down Syndrome

J Ultrasound Med 20:1053–1063, 2001

Adjusted Aneuploidy Risk

www.fetalcenter.org

AAURA.xls

www.perinatology.com

Trisomy 18

CPC

Choroid Plexus Cysts Seen in 33% of Trisomy 18 fetuses

Seen in 2-5% of normals Perform a detailed sonogram

Face, heart, great vessels, extremities An open hand is significant

Meta-analysis In 748 cases of isolated CPC, risk 1/374

In 1016 cases, no cases seen (age < 35)Am J Obstet Gynecol 1995;172:83

Am J Obstet Gynecol 2002;187:1246

Hands, Feet

Trisomy 18 Nuchal thickening Choroid plexus cysts NTDs Cisterna magna, ACC, cerebellar hypoplasia Ventriculomegaly Clenched hands Rocker bottom feet

Strawberry cranium Facial clefts Low set ears Diaphragmatic hernia Omphalocele Renal 2 vessel cord Cord cysts

Trisomy 13

Trisomy 13 Alobar holoprosencephaly Cyclopia, facial clefts Anopthalmia Polycystic kidneys ACC Ventriculomegaly

NTDs Cardiac Polydactyly Nuchal thickening Urogenital Omphalocele

Turner Syndrome

Turner Syndrome

Turner Syndrome Septate cystic hygroma Lymphangiectasia Coarctation Nuchal thickening Short femur

60% of fetuses become hydropic Hydrops + hygroma = near 100% mortality

Triploidy 69xxx (xxy) Severe asymmetric IUGR Small calcified placenta with oligo, vs. … Hydropic placenta (partial mole) Facial defects Holoprosencephaly, Dandy-Walker Syndactyly of 3rd and 4th digits