Sonographic Detection of Aneuploidy Eric H. Dellinger, MD Director, Division of Maternal-Fetal Medicine Greenville Hospital System Greenville, South Carolina

Introduction The Future of Science and Medicine: Exploring the extremes

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 Nuchal translucency (mm) Total nChromosomal defects (%) < , > 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 NTCHD per 1000 < 2.0 mm to 2.4 mm to 3.4 mm6.0 > 3.4 mm 23 Bahado-Singh et al, Am J Obstet Gynecol May;192(5):

NT Technique

Proper CRL is a MSLL MSLL = maximum straight line length

Enlarge

Caliper Placement

NT Increase at 11 – 14 weeks

NT Interpretation From 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 NTPoor Outcome mm 32% mm 49% 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 95 th percentile is a better threshold NT between 95 th and 99 th 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

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 newborns0.5% aneuploid Structural anomalies11% aneuploid Am J Med Genet 1988;29:289

Type of Defect Matters Omphalocele with liver3 of 34 aneuploid Omphalocele without liver12 of 14 aneuploid AJR 1992;158:133; J Ultra Med 1989;8:299

Growth Restriction Finding Aneuploid Isolated IUGR2 % IUGR + anomaly20 % 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 Non Of 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 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 5 th digit Sandal gap Wide iliac angle Short nasal bone

Short Femur and Humerus Expected FL = x BPD Measured/Expected FL ≤ 0.91 is ABNORMAL 53% of Downs 5% of normals Expected HL = x BPD Measured/Expected HL <0.90 is ABNORMAL 48% of Downs 2% of normals

Echogenic Intracardiac Focus % of Downs 4% of Normals % of Asians

Echogenic Bowel 15% of Downs 0.6% of Normals 3.6% aneuploid 2.9% 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 5 th Digit Clinodactyly 19% Downs 3.4% normals 5 th /4 th ratio of 0.70

Sandal Gap Seen in 45% of newborns with Downs Subtle finding on scan

Brachycephaly Shortening of the frontal occipital brain length Smaller frontal lobes Not an effective screen

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

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 AAURA.xls

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

Alobar holoprosencephaly Cyclopia, facial clefts Anopthalmia Polycystic kidneys ACC Ventriculomegaly NTDs Cardiac Polydactyly Nuchal thickening Urogenital Omphalocele

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 3 rd and 4 th digits