1. Micaela Della Torre, MD MS Maternal Fetal Medicine
“Sonographic fetal findings with borderline significance and Down Syndrome”
Micaela Della Torre, MD MS
Maternal Fetal Medicine
Saturday, April 15, 2017

2. Objectives
Learn how to recognize the most common sonographic signs associated with trisomy 21 in the second trimester to improve recognition of affected fetuses
Learn sensitivity, specificity and likelihood ratios of the different signs
Learn how to better use genetic ultrasound in the contest of maternal screening test
Saturday, April 15, 2017

3. I declare that I do not have a financial interest or other relationship with any manufacturers of any commercial products that may be discussed during this presentation
Saturday, April 15, 2017

4. Outlines Screening for Down syndrome and risk assessment NT
NB, tricuspide regurgitation, abnormal ductus venosus
cystic hygroma
Pyelectasis
Hyper-echoic bowel
Ventriculomegaly
Single umbilical artery
Long bones
Others
Saturday, April 15, 2017

5. “Observations on an ethnic classification of idiots” by Langdon Down in 1866
…The hair is not black, as in the real Mongol, but of a brownish color, straight and scanty. The face is flat and broad, and destitute of prominence. The cheeks are roundish, and extended laterally. The eyes are obliquely placed, and the internal canthi more than normally distant from one another. The palpebral fissure is very narrow. The forehead is wrinkled transversely from the constant assistance which the levatores palpebrarum derive from the occipito-frontalis muscle in opening of the eyes. The lips are large and thick with transverse fissures. The tongue is long, thick, and is much roughened. The nose is small. The skin has a slight dirty yellowish tinge, and is deficient in elasticity, giving the appearance of being too large for the body.’ …
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6. Saturday, April 15, 2017

7. Now screening primarily for adjusted risk of chromosomal abnormality
Last three decades major improvement in pregnancy screening for open neural tube defect (ONTD) and aneuploidy
Now screening primarily for adjusted risk of chromosomal abnormality
T18 and T21
Better detection rate of ONTD by ultrasound alone
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8. Chromosomal defects: frequency and occurrence
Natural frequency for chromosomal abnormalities at birth is estimated to be 6:1000
Most common is trisomy 21 (overall 1:700)
The risk of Down syndrome varies drastically w maternal age
USA
women of age
4.7% of live births in 1974
12.6% of live births in 1997
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9. Down syndrome Three separate mechanisms Non disjunction (95%)
95% of non disjunction is maternal in origin
Translocation
Mosaicism
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10. Maternal and paternal age risk
Relationship between age and increased risk was first noticed by Penrose in 1933
Prevalence also increases w paternal age
Fathers more than 39 of age have 3 times higher risk than in father less than 35 of age
True even if adjusted for maternal age
Lansac et al 1997
Jalbert 1995
These are infertility studies
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11. Predictive value of maternal screening alone is poor
1970s  maternal age alone
Predictive value of maternal screening alone is poor
lower than 25%
1 affected fetus over 125 invasive procedures
Even worst now that the proportion of pregnant women over 35 is increasing
Screening protocols allow detection of trisomy21 among younger women and better assessment of the risk in older women
Lets keep in mind that 50 to 60% of fetuses affected by trisomy 21 have a normal ultrasound
Saturday, April 15, 2017

12. method of screening is more effective than maternal age alone
1980s – more tools were introduced to better assess the risk of Down syndrome
maternal age
concentration of various fetoplacental products in the maternal circulation (maternal biochemistry)
a-fetoprotein, estriol, human chorionic gonadotropin (hCG) (total and free-b)
method of screening is more effective than maternal age alone
Screening is becoming more efficient and effective
Using only maternal serum, detection rate is from 55 to 68% - maternal serum markers are very dependent from GA
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13. Now different options are available
Maternal age
Fetal nuchal translucency thickness at 11–14 weeks of gestation
PPV 75% w FP rate 5%
Even more recently
Fetal nuchal translucency
Maternal serum biochemistry
free b-hCG
PAPP-Aabout 90%
PPV 90% w FP rate 5%
Now different options are available
Only in more recent years is that we see the combination of age, ultrasound data and biochemistry data
Last line is SEQUENTIAL versus I trimester screening
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14. Down syndrome detection
First trimester
levels of PAPP-A and free -hCG NT
Detection rate of 85% with 5% false positive rate (FPR)
Second trimester quad screen
levels of AFP, hCG, estriol, and inhibin A
Detection rate of 81% with 5% FPR
Step-wise sequential
Detection rate of 95% with 5% FPR
Quad screening 80% versus with triple screening
First trimester screening also add the benefit of accurate dating
Saturday, April 15, 2017

15. Nuchal translucency
Szabo and Gellen were the first to describe an abnormal nuchal translucency in the first trimester as a marker for Down’s syndrome
Lancet 1990
95% trans abdominally and 5% trans vaginally
US machine of good quality
Most studies have used NT of 3 mm (95th percentile) or 3.5 mm(99th percentile) to define the upper limit of the normal range between 11 and 14 weeks
Calipers - calipers should be able to provide measurements to one decimal point
Uniformity of results among different operators
Reproducible results improve with training 98to 100%
The ability to measure nuchal translucency and obtain reproducible results improves with training -- good results are achieved after 80 and 100 scans transabdominal and the transvaginal respectively
intra-observer and inter-observer differences in measurements were less than 0.5mm in 95% of cases after training – two association FMF and NTQR – quality control
it is best to rely on the mean of two good measurements for the calculation of risk, rather than on a single one
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16. Technique
CRL 39 to 84mm
Sagittal view - magnification should be such that the fetus occupies at least three-quarters of the image
Careful distinguish between fetal skin and amnion
NT should be measured with the fetus in the neutral position –
Hyperextension increase up to 0.6mm
Flexion decrease up to 0.4mm
If umbilical cord is around the neck the NT measurements can be falsely increased
Nuchal translucency measurements are unaffected if the fetus is either in the supine or prone position
Calipers – more than one measurements; largest must be recorded
 in 80% of newborns with trisomy 21
 6 mm, weeks- strongest risk factor for trisomy 21
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17. Saturday, April 15, 2017 What is wrong with this picture?
Good sagittal view
Magnification is too small
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18. Correct magnification Neutral positon
Good sagittal view
Correct magnification
Neutral positon
Amnio can be clearly distinguished by nuchal membrane
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19. Summary of reported series on fetal NT and presence of associated chromosomal defects – early 90s

20. Late 1990,s - detection rate
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21. More recent detection rates
Year N
NT ct-off
FPR
DR for T21
Schuchter 2001
9342
2.5
2.1 58
Wayda 2001
6841
4.1
100
Panburana 2001
2067
2.9
Zoppi 2001
10111
95th percentile
5.1
81.3
Gasiorek-wiens 2001
21959
8.0
82.9
Comas 2002
7345
4.9
Chasen 2003
2246
3.4 75
Brizot 2001
2492
6.4 70
Audibert 2001
4130
3.0
1.7
58.3
Rozemberg 2002
6234
2.8
61.9
Total
72769
81.5
To be noted is that higher is the detection rate the higher is the false positive rate

22. Counseling
Both first trimester and sequential screening have been established as reliable risk assessment tools
Especially if NT is less than 95th percentile
Invasive testing should be offered to all cases of increased NT (3 to 3.5 mm)
If karyotype is normal, fetal echocardiogram should be obtained
FISH for 22q11.2 deletion
If karyotype is normal, normal outcome is expected in more than 85% of cases
If persistent elevated NF later in pregnancy the association with hydrops, demise and major anomalies has been described – however there is no consensus on ANT and intensive surveillance in these fetuses
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23. Association between thickened NT and major cardiac defects
Prevalence of major cardiac defects in normal chromosome fetuses w increased NT – Hyett et al 1996
Year N NT
Cardiac defects
Hyett 1997
1389 mm
≥3.5mm
6/ %
9/ %
Ghi 2001
1319
18/ %
42/597 7%
Lopes 2003
275
2/ %
11/ %
Galindo 2003
353 mm
≥ 4mm
7/ %
25/ %
McAuliffe 2004
177
5/ %
8/ %
Total
3448
38/ %
95/ %
Association between thickened NT and major cardiac defects
NT ≥ 2.5mm  prevalence of major cardiac defects is 17/1000
One third of pregnancies w fetuses affected by major cardiac defects have thickened NT
DR 10 to 56%
FPR 2.5% to 9%
Saturday, April 15, 2017

24. Other markers…
Further improvements in screening performance may be achievable in the future
Nasal Bone
Tricuspid regurgitation by pulsed wave Doppler
Abnormal blood flow through the ductus venosus
ADAM 12 – placental glycoprotein
Other us markers have been studied to be included in screening process
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25. Nasal bone Cicero 2001 and 2003 No correlation w biochemical markers
NB appears to be absent in about 68% of fetuses w Down’s syndrome
Absent only in 1-2% of normal fetuses
No correlation w biochemical markers
DR 96% and FPR 5%
DR 90% and FPR 1%
Technical difficulties
Altered incidence in Afro-Caribbean populations – Cicero 2004
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26. Tricuspid regurgitation
Hurron 2003
Tricuspid regurgitation is present in 8% of normal fetuses and in 65% of T21 fetuses
Independent from serum markers
Falcon 2006
Combined MA/NT/Serum and tricuspid regurgitation
95% DR and 5% FPR (90% DR and 2-3% FPR)
This last value being comparable with DR of sequential screening
On the left, trivial regurgitation
On the right, valve regurgitation in a fetus with an atrioventricular septal defect

27. Abnormal ductus venosus
Ductus venosus is fetal shunt between the portal vein and inferior vena cava
Oxygenated blood from placenta to the heart
Very useful in assessing fetal abnormal cardiac function
Normal ductus venosus Doppler
Pulsatility Index for veins
High velocity during ventricular systole (S-wave)
High velocity during ventricular diastole (D-wave)
Presence of forward flow during atrial contraction (A-wave)
In cardiac failure -with or without cardiac defects- absent or reversed A-wave
Time consuming
Required skilled operators
Likely not for routine screening setting
Reserving invasive testing only for those with abnormal ductal flow

28. Abnormal ductus venosus flow
Mattias et al 1998
Perform ductus venosus Doppler in fetuses with increased NT
Abnormal ductus in 57 of 63 (90.5%) chromosomally abnormal fetuses
Abnormal ductus in 13 of 423 (3.1%) chromosomally normal fetuses
7 of 13 with absent or reversed flow had major cardiac defect demonstrated 14–16 weeks
Saturday, April 15, 2017

29. <95th % 0.2% 1.3% 1.6% 97% 95th-99th % 3.7% 2.5% 93% 3.5-4.5mm
Nuchal
Translucency
Chromosomal
Defects
Fetal Death
Major Fetal
Abnormalities
Alive and
Well
<95th %
0.2%
1.3%
1.6%
97%
95th-99th %
3.7%
2.5%
93% mm
21.1%
2.7%
10.0%
70% mm
33.3%
3.4%
18.5%
50% mm
50.5%
10.1%
24.2%
30%
>6.5mm
64.5%
19.0%
46.2%
15%
Nicolaides, K.H.(2005). The weeks scan. pp 72.

30. What is this?

31. Intracardiac echogenic focus
Micro-calcification within the papillary muscle of the heart
0.5 to 20% - mostly in left ventricle, but it can be right or bilateral
Caucasians 3.5 to 10.5%
AA 5.5 to 5.9%
Asians 10 to 30%
Isolated in low risk population – no increased risk
Likelihood ratio 1.8 – rarely a low risk patient becomes an high risk patient
High risk population or associated with other findings – addition counseling is warranted
Should be as bright as bone to be a true findings
Look for associated anomalies  IEF + hypoplastic left heart is higly suggestive of T13
Compare findings and maternal screening and maternal age
Only 4 % are bilateral, and the association with chromosomal abnormalities is stronger
Saturday, April 15, 2017

32. What is it?
Saturday, April 15, 2017

33. Saturday, April 15, 2017

34. Single Umbilical Artery
0.5-2% of all prenatal ultrasound
caucasian 3 times higher than AA
very rare in Japanese descent
3 to 4 fold increase in twins
Targeted imaging to rule out concurrent anomalies (15-45% associated anomalies)
If other anomalies not seen in utero, 7-10% chance of findings at birth
Associated anomalies-high risk aneuploidy (20-25% to 45% if CNS anomalies)
Isolated SUA in AGA fetus- risk aneuploidy age related - Parilla et al 1995
Some literature suggest slight increase, approximately 1%
Presence of single umbilical artery in newborns was first described in 1543 by Versalius in his De Humani Corporis.
Some studies suggest fetal echo because association with congenital heart defect is high (18-34%)
SUA +cardiac defect+extremeties abnormalities+choroid plexus cysts and IUGR  very high risk of T18
SUA+holoprosencephaly+cleft+cardiac defects+polydactyly  T13
Rule of thumb
Isolated SUA – no increased risk of T21, amnio not indicated
SUA associated with other anomalies – increased risk of chromosomes abnormalities – 50% aneuploidy rate

35. 2 vessels cord
IUGR in as high as 28% of cases of isolated single umbilical artery
Placental anomalies found in 16 to 78% of cases
Most common small placenta and abnormal cord insertion
Perinatal mortality increased after adjustment for associated anomalies
Saturday, April 15, 2017

36. What is it?

37. Mild pelviectasis Distention of fetal renal pelvis by urine
Most often bilateral, when unilateral right more common than left
Up 16% associated with other anomalies
< 4 mm, < 33 weeks
< 7 mm, > 33 weeks
> 10 mm is always pathologic
Common finding – 2-3% in normal fetuses
More common in male than female 2:1
Trisomy 21 – likelihood 1.6
Risk of Uropathy
UPJ obstruction, VUR, primary nonrefluxing megaureter, UVJ obstruction, ectopic ureter, PUV, magacystic megaureter, physiologic dilatation, multicystic dysplastic kidneys, ARPKD, extrophy, prune belly syndrome
Look for other anomalies
Compare with baseline risk

39. Counseling Increased risk of Down syndrome Amniocentesis
If not screening test available, risk is about 1%
If screening test is available, risk is increased slightly compared adjusted maternal risk
Amniocentesis
Repeat ultrasound after 32 weeks
Saturday, April 15, 2017

40. Counseling
30-50% of fetuses with isolated pyelectasis will have normal postnatal course
Vast majority of affected fetuses do not require surgical intervention (99%)
Consider neonatology and pediatric urology evaluation at time of birth
(tertiary center??, evaluation can be delayed to day 2-3 of life)
Saturday, April 15, 2017

41. What is it?
Saturday, April 15, 2017

42. Echogenic bowel Non specific finding
Bowel should have echogenicity similar to bone structures
Gain setting down until other soft tissue cannot be seen – only echogenic bowel and bones
Nyberg classification
Grade 1 moderate diffuse echogenicity
Grade 2 focal echogenicity (more likely to be associated with problems)
Grade 3 very echogenic , as bone
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43. Most cases of isolated finding do have normal outcomes
Simon-Bouy 2003
Prospective study of 682 cases
447 normal outcome (65.5%)
Saturday, April 15, 2017

44. Can be associated with GI anomalies
bowel atresia, anorectal malformations, volvulus, obstruction (2-10%)
CF (2-4%)
Viral infection (3-4%) – CMV, Toxoplasmosis, Parvo B19
Down syndrome
Banasiak 2001 – reviewed of 9 studies 13/380 (3.4%) of echogenic bowel cases had confirmed infections, mostly CMV and Toxo
Simon Buoy 2003 – 15 cases of CMV /682 echogenic bowel (2.2%), 4 Parvo (0.6%)
Saturday, April 15, 2017

45. Aneuploidy risk Bansiak et al 2001 Simon Bouy et al 2003
Cumulative 9.5% aneuploidy (63/663)
Isolated 3% (13/439) and DS was the most common
Simon Bouy et al 2003
Cumulative 4.3% (29/682)
Shipp et al 2002
Increase 5.5 times the a priori risk for DS
Nyberg et al 2001
Likelihood ratio for DS 6.7 if isolated hyperechoic bowel
In absence of these above described association, echogenic bowel has been associated with other visceral anomalies, cardiac malformation, hydrocephalus, skeletal dysplasia, urinary tract anomalies, genetic syndromes
Strocker et al 2000 – fetal swallowing of blood and no additional anomalies carries excellent prognosis

46. Poor obstetrical outcomes
Rochon and Eddleman 2004
14-18% of pregnancies complicated by echogenic bowel also experience growth restriction and IUGR
Increased risk of IUFD and neonatal death
Simon-Bouy 2003
2% unexplained IUFD
Amniocentesis, CF screening, TORCH
Serial ultrasound
ANT
Saturday, April 15, 2017

47. What is it?

48. Ventriculomegaly Width of the atria of the lateral ventricles >10mm
Mild 10-12
Severe >15
1-2/1000
Trisomy 13,18,21; triploidy, umbalanced translocations (4%)
Normal variant
Congenital infection – toxoplasmosis, CMV, syphylis
Absence corpus callosum
Hydrocephalus – aqueductal stenosis, ONTD, Dandy Walker
Detailed or targeted ultrasound
Amniocentesis karyotype, TORCH, MRI of fetal brain??
Prognosis – controversial
If not isolated, depends on other anomalies
Up to 15% progression in utero, up to 55% remains stable and 30% regresses – if resolses in utero  normal outcome
Persistent mild ventriculomegaly is associated with developmental delay in 30% of cases, both motor and cognitive function
Saturday, April 15, 2017

49. Age-adjusted ultrasound risk assessment for trisomy 21
Nyberg 1998
AAURA is a priori risk (MA) X LR resulting from presence or absence of specific US findings for each patient
Lilelihood ratio = sensitivity / false-positive rate as an isolated finding
Case-control study
142 fetuses with trisomy 21 and 930 fetuses with normal karyotype
All patients underwent 2nd trimester US at single institution through standardized US protocol w/o knowledge karyotype
This introduced a new concept
Now there are different calculators available using the a priori screening test risk – but this was the first

52. Age-adjusted ultrasound risk assessment for trisomy 21
AAURA detection rate for DS was 74%
137/930
78.6% (81/103) from women  35
61.5% (24/39) from women < 35
Overall false-positive rate of 14.7%
4% (21/519) for women < 35
28.2% (116/411) for women  35
12.5% (42/337) for women 35-39
100% (74/74) for women  40
Saturday, April 15, 2017

54. References
Textbook of fetal abnormalities 2nd Edition – Peter Twining 2007
Diagnostic Imaging Obstetrics First Edition – Woodward 2005
Diagnostic Imaging of Fetal Anomalies – Nyberg 2003
Diploma in fetal medicine & ISUOG educational series Chapter 1-
Spencer “Aneuploidy in first trimester screening” America Journal of Medicine Genetics Part C: Seminars in medical genetics; Vol 145C, Issue1,
Hyett “Does nuchal translucency have a role in fetal cardiac screening?’ Prenat Diagn 2004; 24:1130
Falcon et al “Screening for trisomy 21 by fetal tricuspid regurgitation, nuchal…”Ultrasound Obstet Gynecol 2006: 27(2); 151
Mavrides et al “Screening for aneuploidy in the first trimester by assessment of blood flow in the ductus venosus” BJOG 2002, vol 109, 1015
Borrell et al “Ductus venosus assessment at the time of nuchal translucency measurement in the detection of fetal aneuploidy” Prenat Diagn 2003; 23(11):921
Muta et al ‘Application of ductus venosus Doppler Velocimetry for the detection of fetal aneuploidy in the first trimester of pregnancy’ Fetal Diagn Ther 2002, 17: 308
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55. Zoppi et al “First trimester dusctus venosus velocimetry in relation to nuchal translucency thickness and fetal karyotype” Fetal Diagn Ther 2002; 17(1):52
Favre et al “The role of fetal nuchal translucency and ductus venosus Doppler at wks of gestation in the detection of major congenital heart defects” Ultrasound Obstet Gynecol 2003; 21(3): 239
Borell et al “First trimester screening for Down sdr with ductus venosus Doppler studies in addition to nuchal translucency and serum markers” Prenat Diagn 2005; 25(10): 901
Devine et al “Nuchal translucency and its relationship to congenital heart disease” Semin Perinatol 2000, 24(5): 343
Neuman et al “ First trimester screening for congenital heart disease” Minerva Cardioangiol 2006; 54(3): 337
Guis F, Y Ville et all “Ultrasound evaluation of the length of the nasal bones throughout gestation” Ultrasound Obstet Gynecol. 5 (1995);
Cicero S, Curcio P et all “Absence of nasal bone in fetuses with trisomy 21 at weeks of gestation: an observational study” Lancet; vol 358; November 17, 2001
Sonek JD and Nicholaides KH “Prenatal ultrasonographic diagnosis of nasal bone abnormalities in three fetuses with Down Syndrome” Am J Obstet Gynecol 2002; 186:
Otano L et al “ Association between first trimester absence of fetal nasal bone on ultrasound and down syndrome” Prenat Diagn 2002; 22:930
Gomez et al “ US measurement of nasal bone in a low risk population at gestational weeks” -Ultrasound Obstet Gynecol 2004; 23: 152
Viora et al “Fetal nasal bone and trisomy 21 in the second trimester” Prenat Diagn 2005: 25; 511
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56. Odibo et al “Association between fetal nasal bone hypoplasia and aneuploidy” Obstet Gynecol 2004; 104: 1229
Cicero et al “Maternal serum biochemistry at wks in relation to the presentcee or absence of the fetal nasal bone on ultrasonography in chromosomally abnormal fetuses: an updated analysis of integrated ultrasound and biochemical screening” Prenat Diagn 2005: 25; 977
Ville “What is the role of fetal nasal bone examination in the assessment of risk for trisomy 21 in clinical practice? AJOB 2006; 195:1
Cicero et al “Nasal bone in first trimester screening for trisomy 21” AJOB 2006: 195:109
Sonek et al “Nasal bone assessment in prenatal screening for trisomy 21” AJOB ; 1219
Weingertner et al “Interest of fetal nasal bone measurement at first trimester Trisomy 21 screening” Fetal Diagn Ther 2006; 21:433
Zoppi et al “Absence of fetal nasal bone and aneuploidies at first trimester nuchal translucency screening in unselected pregnancies” Prenat Diagn 2003; 23:
Cicero et al “ Absence of nasal bone in fetuses with trisomy 21 at wks of gestation: an observational study” Lancet 200: 358, 2001
Snijders et al – ‘ Assessment of risks” Ultrasound markers for fetal chromosomal defects – Parthenon Publishing: Carnforth 1996;
Nicolaides “Screening for chromosomal defects” Ultrasound Obstet Gynecol 2003; 21: 313
Cicero et al “ Likelihood ratio for trisomy 21 in fetuses with absent nasal bone at the wks scan” Ultrasound Obstet Gynecol 2004; 23: 218
Malone et al ‘First trimester nasal bone evaluation for anuploidy in the general polulation” Obstet Gynecol vol 104; No6; December 2004
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57. Thank You and questions???
Saturday, April 15, 2017