ultrasound screening for down syndrome - lieberman's...

Joshua U. Klein, HMS IIIGillian Lieberman, MD

Ultrasound Screening Ultrasound Screening for Down Syndromefor Down Syndrome

Joshua U. KleinJoshua U. KleinHarvard Medical School Year IIIHarvard Medical School Year III

Gillian Lieberman, MDGillian Lieberman, MD

September 2003


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Patient EHPatient EH

35 35 y/oy/o G0P0 G0P0

IVF treatment; now pregnant with IVF treatment; now pregnant with di/didi/di twins, GA by LMP = 13 weeks, 0 daystwins, GA by LMP = 13 weeks, 0 days

Presents with bleedingPresents with bleeding

Undergoes Undergoes transabdominaltransabdominal ultrasoundultrasound

Presenting fetus is Presenting fetus is ““ultrasonically somewhat ultrasonically somewhat increased risk for Downincreased risk for Down”” due to increased due to increased nuchalnuchal translucency translucency


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Down Syndrome: Background IDown Syndrome: Background I

TrisomyTrisomy 21: most common chromosome 21: most common chromosome abnormality among live births (1/730)abnormality among live births (1/730)

Clinical Manifestations:Clinical Manifestations:–– Mental Deficiency (Average IQ 25Mental Deficiency (Average IQ 25--50)50)–– Flat facial profile (90%)Flat facial profile (90%)–– HypotoniaHypotonia (80%)(80%)–– HyperflexibilityHyperflexibility of joints (80%)of joints (80%)–– Upward slanting Upward slanting palpebralpalpebral fissures (80%)fissures (80%)–– Simian crease (45%)Simian crease (45%)–– Congenital heart disease (e.g. Congenital heart disease (e.g. EndocardialEndocardial cushion defect, cushion defect,

VSD VSD –– 40%)40%)


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Down Syndrome: Background IIDown Syndrome: Background II

Pathogenesis: Meiotic nonPathogenesis: Meiotic non--disjunction disjunction increasing risk with advanced maternal ageincreasing risk with advanced maternal age

From www.uptodate.com, adapted from Cuckle, HS et al. BJOG 1987; 94:387

http://www.uptodate.com/


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Screening I: AMA Screening I: AMA

97% of Down pregnancies occur in families with no 97% of Down pregnancies occur in families with no previous history of the syndromeprevious history of the syndrome

Amniocentesis: Effective diagnosis but 1% risk fetal Amniocentesis: Effective diagnosis but 1% risk fetal lossloss

Only 12.9% of all children are born to mothers age Only 12.9% of all children are born to mothers age > 35 > 35

only about 30% of Down babies are born only about 30% of Down babies are born

to to ““AMAAMA”” mothersmothers

Goal: isolate highest risk pregnancies for Goal: isolate highest risk pregnancies for amniocentesis/CVSamniocentesis/CVS


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Screening II: SerumScreening II: Serum

Serum Screening:Serum Screening:–– ““Triple TestTriple Test””: Free B: Free B--hCGhCG, AFP, uE3, AFP, uE3

---- 22ndnd trimestertrimester---- 69% sensitive69% sensitive---- 9.3% false positive9.3% false positive

---- ““Quadruple TestQuadruple Test””: Triple Test + : Triple Test + inhibininhibin AA---- 22ndnd trimestertrimester---- 80% sensitive80% sensitive---- 6.2% false positive6.2% false positive


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Screening III: Screening III: NuchalNuchal TranslucencyTranslucency

Best overall screening test: Best overall screening test: Quadruple test (2Quadruple test (2ndnd trimester) + PAPPtrimester) + PAPP--A (1A (1stst trimester) + NT trimester) + NT at 10 weeks at 10 weeks

85% sensitivity, 1.2% false85% sensitivity, 1.2% false--positive ratepositive rate

From www.uptodate.com adapted from Wald NJ, et al. J Med Screen 1997; 4:181.



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Ultrasound: Basics IUltrasound: Basics I

Current is applied to a Current is applied to a transducer made of transducer made of piezoelectric crystal, piezoelectric crystal, generating highgenerating high--frequency frequency sound waves which pass sound waves which pass through the soft tissuethrough the soft tissue

Interface of different densities Interface of different densities (acoustic impedance) reflects (acoustic impedance) reflects some of the energy, some of the energy, proportional to the difference proportional to the difference in densitiesin densities

The reflected energy generates The reflected energy generates small voltage, amplified and small voltage, amplified and represented by light/dark on represented by light/dark on screen screen

Bone, air, fat: whiteBone, air, fat: white

Fluid: darkFluid: dark

Solid organs: greySolid organs: grey


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Ultrasound: Basics IIUltrasound: Basics II

Advantages:Advantages:–– No ionizing radiation No ionizing radiation

pregnancypregnancy–– Any planeAny plane–– InexpensiveInexpensive–– Portable Portable -- bedsidebedside–– RealReal--time imagestime images

Disadvantages:Disadvantages:–– Fuzzy imagesFuzzy images–– SkillSkill--dependentdependent


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Routine UltrasoundRoutine Ultrasound

1111--14 weeks14 weeks

Assess:Assess:---- Viability, number, sizeViability, number, size---- Anatomy:Anatomy:

---- Head/Brain (BPD, HC)Head/Brain (BPD, HC)---- Cardiac Cardiac ---- Abdomen (stomach, bowel, AC)Abdomen (stomach, bowel, AC)---- Urinary (bladder, kidneys)Urinary (bladder, kidneys)---- Limbs (FL, HL)Limbs (FL, HL)


1111

NuchalNuchal Translucency MeasurementTranslucency Measurement

Increase in the size of the normal, clear area behind the fetal Increase in the size of the normal, clear area behind the fetal neck (>2.5 mm or 95neck (>2.5 mm or 95thth percentile)percentile)

Optimal time: 11Optimal time: 11--13 weeks13 weeks

TransabdominalTransabdominal or or transvaginaltransvaginal

SagittalSagittal SectionSection

Magnification: Fetus should occupy 75% of the imageMagnification: Fetus should occupy 75% of the image

Distinguish between fetal skin and amnionDistinguish between fetal skin and amnion

Fetus in neutral position (i.e. not flexed/extended)Fetus in neutral position (i.e. not flexed/extended)

From http://www.nuchalscans.co.uk/images/scan2.gif


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NTNT

Normal NT Increased NT

From www.uptodate.com http://womenshealth.jhmi.edu/ob-ultrasound/services/nts.html


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NT PathophysiologyNT Pathophysiology

Cardiac malformation/dysfunctionCardiac malformation/dysfunction

Alterations in the extracellular matrixAlterations in the extracellular matrix

Lymphatic abnormalitiesLymphatic abnormalities

Precise etiology remains unknownPrecise etiology remains unknown


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PACS, BIDMC


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Patient EH: Twin APatient EH: Twin A

PACS, BIDMC


1616

Patient EH: Twin BPatient EH: Twin B

PACS, BIDMC


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NT: NT: ““Dose ResponseDose Response””

Increased incidence of Increased incidence of trisomiestrisomies 21, 18, and 21, 18, and 13:13:

NT = 3mm NT = 3mm

3X3XNT = 4mm NT = 4mm

18X18X

NT = 5mm NT = 5mm

28X28XNT = >6mm NT = >6mm

36X36X

Patient EH, Twin A: Only mildly increased Patient EH, Twin A: Only mildly increased NT (2.6mm) NT (2.6mm)

mildly increased riskmildly increased risk

Recommend Recommend ““quadruple testquadruple test””


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Other US Other US ““soft markerssoft markers””

Frequently found among normal fetuses; Frequently found among normal fetuses; should not be used in isolation for Down should not be used in isolation for Down screeningscreening

Useful in combination with serum screening Useful in combination with serum screening and NT to modify riskand NT to modify risk

---- Shortened Shortened humerushumerus/femur/femur---- HyperechoicHyperechoic bowelbowel---- HypoplasticHypoplastic nasal bonenasal bone---- EndocardialEndocardial cushion defectcushion defect---- PyelectasisPyelectasis


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““Soft MarkersSoft Markers””

Nicolaides KH, Snijders RJM, Gosden CM, Berry C, Campbell S. Ultrasonographicallydetectable markers of fetal chromosomal abnormalities. Lancet 1992;340:704–7


2020

Patient LGPatient LG

Echogenic BowelPACS, BIDMC


2121


Short femurPACS, BIDMC


2222


Renal dilatationPACS, BIDMC


2323

Normal 4Normal 4--Chamber HeartChamber Heart

www.thefetus.net


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Patient SSPatient SS

PACS, BIDMC

Endocardial Cushion Defect


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Normal nasal bonePACS, BIDMC


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Nasal Bone Nasal Bone HypoplasiaHypoplasia

Present in 62% of Present in 62% of trisomytrisomy 21 fetuses, 1.2% 21 fetuses, 1.2% chromosomally normal fetuseschromosomally normal fetuses

Increased NT

Absent nasal bone

http://www.femalepatient.com/html/arc/sel/sept02/article01.asp

Cicero, S et al. Ultrasound Obstet Gynecol 2003; 21:15-18


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Differential DiagnosisDifferential Diagnosis

SmithSmith--LemliLemli--OptizOptiz syndromesyndrome

MeckelMeckel syndromesyndrome

IniencephalyIniencephaly

CardiosplenicCardiosplenic syndromessyndromes

TORCH infectionsTORCH infections

Normal pregnancyNormal pregnancy


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Integrated screeningIntegrated screening


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Integrated ScreeningIntegrated Screening

KH Nicolaides, NJ Sebire, RJM Snijders for www.thefetus.net


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Age = 35 Age = 35

1:2741:274

Increased NT Increased NT

1:151:15

Advise quadruple serum screenAmniocentesis/CVS


3131


Age = 40 Age = 40

1:741:74

EchogenicEchogenic bowel bowel

1:131:13

+Short femur +Short femur

1:4.51:4.5

Amniocentesis/CVS


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Age = 28 Age = 28

1:8551:855

EndocardialEndocardial cushion defect cushion defect

1:34.51:34.5

Advise quadruple serum screenAmniocentesis/CVS


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ACOG Recommendations ACOG Recommendations (2001)(2001)

““A combination of one major or two minor A combination of one major or two minor ultrasound markers of Down syndrome ultrasound markers of Down syndrome substantially increases risk and warrants substantially increases risk and warrants further counseling regarding invasive further counseling regarding invasive testingtesting””

““The use of The use of ultrasonographicultrasonographic screening for screening for Down syndrome in highDown syndrome in high--risk women (risk women (egeg women age 35 years and older) to avoid women age 35 years and older) to avoid invasive testing should be limited to invasive testing should be limited to specialized centersspecialized centers””


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SummarySummary

The challenge of screening for Down The challenge of screening for Down syndrome is one of risksyndrome is one of risk--assessmentassessment

UltrasonographicUltrasonographic markers such as NT can markers such as NT can significantly alter a patientsignificantly alter a patient’’s risk assessments risk assessment

Integrated screening Integrated screening ---- US combined with US combined with maternal age and serum screening maternal age and serum screening ---- provides a sensitive and specific screen for provides a sensitive and specific screen for Down syndromeDown syndrome


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ReferencesReferences

BencerrafBencerraf, B. Ultrasound in Obstetrics and Gynecology 2000 Jun; , B. Ultrasound in Obstetrics and Gynecology 2000 Jun; 15(6):45115(6):451

Benacerraf, B. Prenatal Diagnosis 2002; 22: 798Benacerraf, B. Prenatal Diagnosis 2002; 22: 798--801801

BindraBindra R, et al. R, et al. ClinClin ObstetObstet GynecolGynecol 2002 Sep; 45(3):6612002 Sep; 45(3):661--670670

CanickCanick, JA., et al. , JA., et al. ““First Trimester Screening for Down SyndromeFirst Trimester Screening for Down Syndrome”” on on www.uptodate.comwww.uptodate.com

CuckleCuckle, HS, et al. British Journal of Obstetrics and , HS, et al. British Journal of Obstetrics and GynaecologyGynaecology 1987; 94:3871987; 94:387

CuckleCuckle, H. , H. CurrCurr OpinOpin ObstetObstet GynecolGynecol 2001 Apr; 13(2):1752001 Apr; 13(2):175--181181

HaakHaak, MC, et al. Human Reproduction Update 2003; 9(2):175, MC, et al. Human Reproduction Update 2003; 9(2):175--184184

HobbinsHobbins, JC et al. J Ultrasound Med 2001 Jun; 20(6):269, JC et al. J Ultrasound Med 2001 Jun; 20(6):269--7272

Jameson, LJ HarrisonJameson, LJ Harrison’’s Textbook of Internal Medicine.s Textbook of Internal Medicine.

Nyberg, DA et al. Ultrasound Nyberg, DA et al. Ultrasound ObstetObstet GynecolGynecol 1998;12:81998;12:8--1414

Nyberg, DA et al. J Ultrasound Med 2001 Jun; 20(6):665Nyberg, DA et al. J Ultrasound Med 2001 Jun; 20(6):665--7474

SnijdersSnijders R, et al. R, et al. CurrCurr OpinOpin ObstetObstet GynecolGynecol 2002 Dec; 14(6):5772002 Dec; 14(6):577--8585



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AcknowledgementsAcknowledgements

Larry Larry BarbarasBarbaras, our Webmaster, our Webmaster

David QuinlanDavid Quinlan

Pamela Pamela LepkowskiLepkowski

Michelle Swire, MDMichelle Swire, MD

Gillian Lieberman, MDGillian Lieberman, MD

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