“sonographic fetal findings with borderline significance and down syndrome” micaela della torre,...

“Sonographic fetal findings with borderline significance and

Down Syndrome”

Micaela Della Torre, MD MSMaternal Fetal Medicine

Tuesday, April 18, 2023

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



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

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


“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.’ …


Last three decades major improvement in pregnancy screening for open neural tube defect (ONTD) and aneuploidy

Now screening primarily for adjusted risk of chromosomal abnormalityT18 and T21

Better detection rate of ONTD by ultrasound alone


Chromosomal defects: frequency and occurrence

Natural frequency for chromosomal abnormalities at birth is estimated to be 6:1000Most common is trisomy 21 (overall 1:700)

The risk of Down syndrome varies drastically w maternal age

USA women 35-49 of age

4.7% of live births in 1974 12.6% of live births in 1997


Down syndrome

Three separate mechanisms

Non disjunction (95%) 95% of non disjunction is maternal in origin

Translocation Mosaicism


Maternal and paternal age riskRelationship between age

and increased risk was first noticed by Penrose in 1933

Prevalence also increases w paternal ageFathers 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 1997Jalbert 1995


1970s maternal age alonePredictive value of maternal screening alone is

poorlower than 25%1 affected fetus over 125 invasive proceduresEven worst now that the proportion of pregnant

women over 35 is increasingScreening protocols allow detection of

trisomy21 among younger women and better assessment of the risk in older women


1980s – more tools were introduced to better assess the risk of Down syndromematernal ageconcentration 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


1990sMaternal ageFetal nuchal translucency thickness at 11–14 weeks

of gestationPPV 75% w FP rate 5%

Even more recently Maternal age Fetal nuchal translucencyMaternal serum biochemistry

free b-hCGPAPP-Aabout 90%

PPV 90% w FP rate 5% Now different options are available


Down syndrome detection

First trimesterlevels 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 ADetection rate of 81% with 5% FPR

Step-wise sequentialDetection rate of 95% with 5% FPR


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


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


Summary of reported series on fetal NT and presence of associated chromosomal defects – early 90s

Late 1990,s - detection rate


More recent detection rates

Year N NT ct-off FPR DR for T21

Schuchter 2001 9342 2.5 2.1 58

Wayda 2001 6841 2.5 4.1 100

Panburana 2001 2067 2.5 2.9 100

Zoppi 2001 10111 95th percentile 5.1 81.3

Gasiorek-wiens 2001 21959 95th percentile 8.0 82.9

Comas 2002 7345 95th percentile 4.9 100

Chasen 2003 2246 95th percentile 3.4 75

Brizot 2001 2492 95th percentile 6.4 70

Audibert 2001 4130 3.0 1.7 58.3

Rozemberg 2002 6234 3.0 2.8 61.9

Total 72769 4.1 81.5

CounselingBoth first trimester and sequential screening

have been established as reliable risk assessment toolsEspecially 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 obtainedFISH for 22q11.2 deletion

If karyotype is normal, normal outcome is expected in more than 85% of cases


Year N NT Cardiac defectsHyett 1997 1389 2.5-3.4mm

≥3.5mm6/1102 .54%9/287 3.14%

Ghi 2001 1319 2.5-3.4mm≥3.5mm

18/722 2.5%42/597 7%

Lopes 2003 275 2.5-3.4mm≥3.5mm

2/159 1.26%11/51 21.5%

Galindo 2003 353 2.5-3.9mm≥ 4mm

7/131 5.34%25/222 11.26%

McAuliffe 2004 177 2.5-3.4mm≥3.5mm

5/122 4.1%8/55 14.5%

Total 3448 38/2236 1.7%95/1212 7.84%Tuesday, April 18, 2023

Prevalence of major cardiac defects in normal chromosome fetuses w increased NT – Hyett et al 1996

Other markers…

Further improvements in screening performance may be achievable in the futureNasal BoneTricuspid regurgitation by pulsed wave Doppler Abnormal blood flow through the ductus venosus

ADAM 12 – placental glycoprotein


Nasal bone

Cicero 2001 and 2003NB 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 markersDR 96% and FPR 5% DR 90% and FPR 1%

Technical difficulties Altered incidence in Afro-Caribbean populations

– Cicero 2004Tuesday, April 18, 2023

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)

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

Abnormal ductus venosus flowMattias et al 1998Perform ductus venosus Doppler in fetuses

with increased NTAbnormal ductus in 57 of 63 (90.5%)

chromosomally abnormal fetusesAbnormal ductus in 13 of 423 (3.1%)

chromosomally normal fetuses7 of 13 with absent or reversed flow had major cardiac

defect demonstrated 14–16 weeks


Nuchal

Translucency

Chromosomal

Defects

Fetal Death

Major Fetal

Abnormalities

Alive and

Well

<95th % 0.2% 1.3% 1.6% 97%

95th-99th % 3.7% 1.3% 2.5% 93%

3.5-4.5mm 21.1% 2.7% 10.0% 70%

4.5-5.4mm 33.3% 3.4% 18.5% 50%

5.5-6.4mm 50.5% 10.1% 24.2% 30%

>6.5mm 64.5% 19.0% 46.2% 15%Nicolaides, K.H.(2005). The 11-13+6 weeks scan. pp 72.

What is this?

Intracardiac echogenic focusMicro-calcification within the papillary muscle of

the heart0.5 to 20% - mostly in left ventricle, but it can be

right or bilateralCaucasians 3.5 to 10.5%AA 5.5 to 5.9%Asians 10 to 30%

Isolated in low risk population – no increased riskLikelihood ratio 1.8 – rarely a low risk patient becomes an high

risk patientHigh risk population or associated with other findings –

addition counseling is warranted


What is it?


Single Umbilical Artery0.5-2% of all prenatal ultrasound

caucasian 3 times higher than AAvery rare in Japanese descent3 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 birthAssociated anomalies-high risk aneuploidy (20-25% to

45% if CNS anomalies)Isolated SUA in AGA fetus- risk aneuploidy age related

- Parilla et al 1995Some literature suggest slight increase, approximately

1%

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


What is it?

Mild pelviectasisDistention 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 pathologicCommon finding – 2-3% in normal fetuses

More common in male than female 2:1Trisomy 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

Counseling

Increased risk of Down syndrome If not screening test available, risk is about 1%If screening test is available, risk is increased

slightly compared adjusted maternal riskAmniocentesisRepeat ultrasound after 32 weeks


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)


What is it?


Echogenic bowelNon specific findingBowel should have echogenicity similar to bone

structuresGain setting down until other soft tissue cannot be

seen – only echogenic bowel and bonesNyberg classification

Grade 1 moderate diffuse echogenicityGrade 2 focal echogenicity (more likely to be associated

with problems)Grade 3 very echogenic , as bone


Most cases of isolated finding do have normal outcomes

Simon-Bouy 2003Prospective study of 682 cases447 normal outcome (65.5%)


Can be associated with GI anomaliesbowel atresia, anorectal

malformations, volvulus, obstruction (2-10%)

CF (2-4%)Viral infection (3-4%) – CMV,

Toxoplasmosis, Parvo B19Down syndrome


Aneuploidy riskBansiak et al 2001

Cumulative 9.5% aneuploidy (63/663)Isolated 3% (13/439) and DS was the most

commonSimon Bouy et al 2003

Cumulative 4.3% (29/682)Shipp et al 2002

Increase 5.5 times the a priori risk for DSNyberg et al 2001

Likelihood ratio for DS 6.7 if isolated hyperechoic bowel

Poor obstetrical outcomesRochon and Eddleman 2004

14-18% of pregnancies complicated by echogenic bowel also experience growth restriction and IUGR

Increased risk of IUFD and neonatal deathSimon-Bouy 2003

2% unexplained IUFDAmniocentesis, CF screening, TORCHSerial ultrasoundANT


What is it?

VentriculomegalyWidth of the atria of the lateral ventricles >10mm

Mild 10-12Severe >15

1-2/1000Trisomy 13,18,21; triploidy, umbalanced

translocations (4%)Normal variantCongenital infection – toxoplasmosis, CMV, syphylisAbsence corpus callosumHydrocephalus – aqueductal stenosis, ONTD, Dandy

WalkerTuesday, April 18, 2023

Age-adjusted ultrasound risk assessment for trisomy 21

AAURA is a priori risk (MA) X LR resulting from presence or absence of specific US findings for each patientLilelihood ratio = sensitivity / false-positive rate

as an isolated findingCase-control study

142 fetuses with trisomy 21 and 930 fetuses with normal karyotypeAll patients underwent 2nd trimester US at single

institution through standardized US protocol w/o knowledge karyotype

Nyberg 1998

Age-adjusted ultrasound riskassessment 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

References1. Textbook of fetal abnormalities 2nd Edition – Peter Twining 20072. Diagnostic Imaging Obstetrics First Edition – Woodward 20053. Diagnostic Imaging of Fetal Anomalies – Nyberg 20034. Diploma in fetal medicine & ISUOG educational series Chapter 1-www.centrus.com5. Spencer “Aneuploidy in first trimester screening” America Journal of Medicine

Genetics Part C: Seminars in medical genetics; Vol 145C, Issue1, 18-32- 20076. Hyett “Does nuchal translucency have a role in fetal cardiac screening?’ Prenat Diagn

2004; 24:11307. Falcon et al “Screening for trisomy 21 by fetal tricuspid regurgitation,

nuchal…”Ultrasound Obstet Gynecol 2006: 27(2); 1518. Mavrides et al “Screening for aneuploidy in the first trimester by assessment of

blood flow in the ductus venosus” BJOG 2002, vol 109, 10159. Borrell et al “Ductus venosus assessment at the time of nuchal translucency

measurement in the detection of fetal aneuploidy” Prenat Diagn 2003; 23(11):92110. 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


11. Zoppi et al “First trimester dusctus venosus velocimetry in relation to nuchal translucency thickness and fetal karyotype” Fetal Diagn Ther 2002; 17(1):52

12. Favre et al “The role of fetal nuchal translucency and ductus venosus Doppler at 11-14 wks of gestation in the detection of major congenital heart defects” Ultrasound Obstet Gynecol 2003; 21(3): 239

13. 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

14. Devine et al “Nuchal translucency and its relationship to congenital heart disease” Semin Perinatol 2000, 24(5): 343

15. Neuman et al “ First trimester screening for congenital heart disease” Minerva Cardioangiol 2006; 54(3): 337

16. Guis F, Y Ville et all “Ultrasound evaluation of the length of the nasal bones throughout gestation” Ultrasound Obstet Gynecol. 5 (1995); 304-307

17. Cicero S, Curcio P et all “Absence of nasal bone in fetuses with trisomy 21 at 11-14 weeks of gestation: an observational study” Lancet; vol 358; November 17, 2001

18. Sonek JD and Nicholaides KH “Prenatal ultrasonographic diagnosis of nasal bone abnormalities in three fetuses with Down Syndrome” Am J Obstet Gynecol 2002; 186: 139-41

19. Otano L et al “ Association between first trimester absence of fetal nasal bone on ultrasound and down syndrome” Prenat Diagn 2002; 22:930

20. Gomez et al “ US measurement of nasal bone in a low risk population at 19-22 gestational weeks” -Ultrasound Obstet Gynecol 2004; 23: 152

21. Viora et al “Fetal nasal bone and trisomy 21 in the second trimester” Prenat Diagn 2005: 25; 511


22. Odibo et al “Association between fetal nasal bone hypoplasia and aneuploidy” Obstet Gynecol 2004; 104: 1229

23. Cicero et al “Maternal serum biochemistry at 11-13 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

24. 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

25. Cicero et al “Nasal bone in first trimester screening for trisomy 21” AJOB 2006: 195:109

26. Sonek et al “Nasal bone assessment in prenatal screening for trisomy 21” AJOB 2006 195; 1219

27. Weingertner et al “Interest of fetal nasal bone measurement at first trimester Trisomy 21 screening” Fetal Diagn Ther 2006; 21:433

28. Zoppi et al “Absence of fetal nasal bone and aneuploidies at first trimester nuchal translucency screening in unselected pregnancies” Prenat Diagn 2003; 23: 496-500

29. Cicero et al “ Absence of nasal bone in fetuses with trisomy 21 at 11-14 wks of gestation: an observational study” Lancet 200: 358, 2001

30. Snijders et al – ‘ Assessment of risks” Ultrasound markers for fetal chromosomal defects – Parthenon Publishing: Carnforth 1996; 63-120

31. Nicolaides “Screening for chromosomal defects” Ultrasound Obstet Gynecol 2003; 21: 313

32. Cicero et al “ Likelihood ratio for trisomy 21 in fetuses with absent nasal bone at the 11-14 wks scan” Ultrasound Obstet Gynecol 2004; 23: 218

33. Malone et al ‘First trimester nasal bone evaluation for anuploidy in the general polulation” Obstet Gynecol vol 104; No6; December 2004


Thank You and questions???


“sonographic fetal findings with borderline significance and down syndrome” micaela della torre,...

Documents

s maternal age

presentation slide

age true

maternal age lansac

paternal age risk relationship

w maternal age usa women

pregnancy screening

increased risk