prenatal testing for down syndrome: where do we stand today? david b. fox, md riverside methodist...
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Prenatal Testing for Prenatal Testing for Down Syndrome: Down Syndrome:
Where Do We Stand Where Do We Stand Today?Today?
David B. Fox, MDDavid B. Fox, MD
Riverside Methodist HospitalRiverside Methodist Hospital
Down SyndromeDown SyndromePhenotype abnormalitiesPhenotype abnormalities
Mental retardationMental retardation
Cardiac defectsCardiac defects
LeukemiaLeukemia
Alzheimer'sAlzheimer's
Visual/hearing Visual/hearing impairmentimpairment
Intestinal Intestinal malformationsmalformations
Shortened life spanShortened life span
Why is Prenatal Testing Why is Prenatal Testing Important?Important?
Peace of mindPeace of mind
EducationEducation
Emotional preparationEmotional preparation
Neonatal issuesNeonatal issues
TerminationTermination
Increased Risk of Fetal Increased Risk of Fetal AneuploidyAneuploidy
Previous fetus or child with Previous fetus or child with autosomal trisomyautosomal trisomy or or sex sex chromosome abnormalitychromosome abnormality
One majorOne major or or two minortwo minor fetal fetal structural defectsstructural defects on ultrasound on ultrasound
Either parent with Either parent with chromosomal chromosomal translocation or inversion translocation or inversion
Parental aneuploidyParental aneuploidy
Is Prenatal Testing for Is Prenatal Testing for Everyone?Everyone?
Prenatal TestingPrenatal Testing
ScreeningScreening versus versus DiagnosisDiagnosis
First trimesterFirst trimester versus versus Second Second trimestertrimester
SerumSerum and/or and/or UltrasoundUltrasound
Low-riskLow-risk versus versus High-risk WomenHigh-risk Women
Diagnostic TestsDiagnostic Tests
First trimesterFirst trimesterCVSCVS
TCTC 10 0/7 - 12 6/7 wks10 0/7 - 12 6/7 wks
TATA 10 0/7 - Term (if anterior 10 0/7 - Term (if anterior placenta)placenta)
Second trimesterSecond trimesterAmniocentesisAmniocentesis
15 0/7 - Delivery15 0/7 - Delivery
Procedure-related RisksProcedure-related Risks
AmniocentesisAmniocentesis
Pregnancy loss Pregnancy loss 1:300-1:5001:300-1:500
Spotting or leakage Spotting or leakage
1-2%1-2% Needle injury - rareNeedle injury - rare Infection - rareInfection - rare
CVSCVS
Pregnancy loss - Pregnancy loss - similar to similar to amniocentesis amniocentesis (TA=TC)(TA=TC)
Spotting - up to Spotting - up to 32% (TC)32% (TC)
Leakage or Leakage or infection - less infection - less than 0.5%than 0.5%
ScreeningScreening
Second trimesterSecond trimester
Maternal age Maternal age Triple screen (AFP, HCG, estriol)Triple screen (AFP, HCG, estriol)
Quad (Triple + Quad (Triple + inhibininhibin))UltrasoundUltrasound
Gestational Age (wk)Gestational Age (wk)
1212 1616 4040
2020 10681068 12001200 15271527
3030 626626 703703 895895
3535 249249 280280 356356
4242 3838 4343 5555
Maternal Age (y)
Adapted from Nicolaides, AJOG, 2004
““Age-Based” ScreeningAge-Based” Screening
Old storyOld story5% of pregnant women 5% of pregnant women >> 35 yo 35 yo
80% DS babies born to younger women80% DS babies born to younger women
New storyNew story14% of pregnant women 14% of pregnant women >> 35 yo 35 yo
70% DS born to younger women70% DS born to younger women
Second Trimester MSAFPSecond Trimester MSAFP
Merkatz, 1984Merkatz, 1984Case report: Serendipitous discovery of Case report: Serendipitous discovery of
low MSAFP in case of T18 led to low MSAFP in case of T18 led to discovery of discovery of low MSAFPlow MSAFP associated withassociated with fetal trisomyfetal trisomy
Sensitivity 20% for DSSensitivity 20% for DS
Age + MSAFP = 40% DS detectionAge + MSAFP = 40% DS detection
Second TrimesterSecond TrimesterTripleTriple Screen Screen
MSAFP + HCG + Estriol MSAFP + HCG + Estriol
0%10%20%30%40%50%60%70%80%90%
100%
False Positive
Sensitivity
65%
5%
Second TrimesterSecond TrimesterQuadQuad ScreenScreen
Triple screen + Triple screen + inhibininhibin
75 –80% DS detection75 –80% DS detection
5% false positive rate5% false positive rate
Second TrimesterSecond TrimesterUltrasound MarkersUltrasound Markers
15-20 weeks15-20 weeks
Thickened nuchal Thickened nuchal foldfold
PyelectasisPyelectasis
Echogenic bowelEchogenic bowel
Short long bonesShort long bones
Congenital anomalyCongenital anomaly
Hypoplastic 5Hypoplastic 5thth digit digit
Ear lengthEar length
Echogenic Echogenic intracardiac focusintracardiac focus
22ndnd Trimester Trimester Nasal Bone Screening Nasal Bone Screening
AbsentAbsent NBNB7 studies: 7 studies: 37%37% prevalence in T21, prevalence in T21, 0.9%0.9% in in
euploideuploid
ShortShort NBNB6 studies: 6 studies: 48.2%48.2% prevalence in T21, prevalence in T21, 2.4%2.4% in in
euploideuploid
ShortShort or or AbsentAbsent NBNB
6 studies: 6 studies: 60%60% prevalence in T21, prevalence in T21, 1.4%1.4% in in euploideuploid
Second TrimesterSecond TrimesterUltrasoundUltrasound
Up to Up to 75%75% of DS fetus will have a of DS fetus will have a markermarker
Therefore, Therefore, 25%25% will have a will have a normal normal ultrasoundultrasound
ProblemsProblems with Second with Second Trimester UltrasoundTrimester Ultrasound
Poor specificityPoor specificity
SubjectiveSubjective
Technical limitationsTechnical limitations
Variability of gestational ageVariability of gestational age
Defect Aneuploidy RiskMost Common Aneuploidies
Cystic hygroma
60-75% 45X,21
Hydrops 30-80% 13,21,18
Cardiac defect
5-30% 13,18
AV canal defect
40-70% 21
Duodenal atresia
20-30% 21
Aneuploidy Risk for Major Anomalies
ADAPTED FROM SLIPP AND BENACERRAF (1990)
First trimesterFirst trimester ScreeningScreening
Nuchal translucency Nuchal translucency
Free beta HCGFree beta HCG
PAPP-APAPP-A
CombinedCombined NTNT and and SerumSerum
Increased Nuchal Increased Nuchal ThicknessThickness
Thickened NTThickened NTwith Normal Karyotypewith Normal Karyotype
Thickened NTThickened NTwith Normal Karyotypewith Normal Karyotype
Thickened NTThickened NTwith Normal Karyotypewith Normal Karyotype
First-Trimester or Second-First-Trimester or Second-Trimester Screening, or Trimester Screening, or Both, for Down’s Syndrome Both, for Down’s Syndrome ((FASTER Trial)FASTER Trial)
Malone et al, NEJM, 2005Malone et al, NEJM, 200515 U.S. Centers15 U.S. Centers38,167 women with singletons enrolled38,167 women with singletons enrolled117 cases of DS117 cases of DSCRL 36-79mm (10 3/7 – 13 6/7 wks)CRL 36-79mm (10 3/7 – 13 6/7 wks)
NT NT + + free beta HCG free beta HCG + + PAPP-APAPP-A (1:150) (1:150)15-18 wks Quad screen15-18 wks Quad screen (1:300) (1:300)
FASTER TrialFASTER Trial
First trimester with 5% FPFirst trimester with 5% FP
11/12/1311/12/13 (wks) (wks)
NTNT 70/68/6470/68/64
Free beta HCG/PAPP-A Free beta HCG/PAPP-A 70/67/6570/67/65
CombinedCombined87/85/87/85/82*82*
*similar to Quad screen at 13 wks*similar to Quad screen at 13 wks
First First andand Second Second TrimesterTrimester
Sequential Sequential independentindependent
Sequential Sequential step-wisestep-wise
Serum integratedSerum integrated
Fully integratedFully integrated
Sequential Sequential contingentcontingent
Faster TrialFaster TrialSequential Sequential independentindependent
11/12/1311/12/13 (wks) (wks)11stst: : Combined NT/SerumCombined NT/Serum 87%/85%/82%87%/85%/82%
22ndnd: : Triple/QuadTriple/Quad 69%/81% detection rates69%/81% detection rates
CalculateCalculate separatelyseparately
Not recommended because (1) Not recommended because (1) high false high false positive ratepositive rate and (2) and (2) aa prioripriori risk not re- risk not re-adjustedadjusted
Faster TrialFaster TrialSequentialSequential Step-wise Step-wise
FullyFully IntegratedIntegrated
First trimester NT/serum First trimester NT/serum PLUSPLUS Second Second trimester Quadtrimester Quad
Blind patientBlind patient to initial result until completion to initial result until completion of Quad. Then give of Quad. Then give single risksingle risk. Exclude . Exclude those with cystic hygoma.those with cystic hygoma.
11/12/1311/12/13 (wks)(wks)
Detection rate (%):Detection rate (%): 96/95/9496/95/94
FullyFully IntegratedIntegrated
““Potential” problemsPotential” problems
Both parts requiredBoth parts required
Loss of follow-up (potential litigation)Loss of follow-up (potential litigation)
Physician/patient reluctance to withhold Physician/patient reluctance to withhold informationinformation
Precludes early terminationPrecludes early termination
ContingentContingent
First-trimester Screen
High Risk Intermediate Risk Low Risk
Offer CVS Quad Screen No Further Testing
Offer Amino if HR
11stst Trimester Trimester “Absent” Nasal Bone“Absent” Nasal Bone
Usefulness controversialUsefulness controversial 3 European studies:3 European studies:
Down Syndrome sensitivity: 66.7-80% in Down Syndrome sensitivity: 66.7-80% in high-risk women (0.2-1.4% FP rate) women (0.2-1.4% FP rate)
Some studies show poor performance in general population
Issues with Nasal Bone Issues with Nasal Bone ScreeningScreening
Correct techniqueCorrect technique Significance of ethnicitySignificance of ethnicity
AbsentAbsent NBNB seen in 2.8% Caucasians, seen in 2.8% Caucasians, 6.8% Asians, 10.4% Afro-Carribeans6.8% Asians, 10.4% Afro-Carribeans
Optimal population (HR vs. LR)Optimal population (HR vs. LR) Optimal gestational ageOptimal gestational age
Nasal bone Nasal bone presentpresent Sonek, 2006Sonek, 2006
Nasal bone Nasal bone absentabsent Sonek, 2006Sonek, 2006
First-Trimester First-Trimester ScreeningScreening
ProsPros Higher detection rateHigher detection rate
Earlier detectionEarlier detection
Safer terminationSafer termination
NT identifies HR NT identifies HR fetusesfetuses
Less bondingLess bonding
More privacyMore privacy
ConsCons Cost ($600 – 700)Cost ($600 – 700)
Unnecessary Unnecessary terminationtermination
Unwanted Unwanted informationinformation
NTD LabNTD Lab
US: CRLUS: CRL 45 – 84 mm (11 1/7- 13 6/7 wks)45 – 84 mm (11 1/7- 13 6/7 wks)
Blood: 9 0/7 – 13 6/7 wks Blood: 9 0/7 – 13 6/7 wks
Instant Risk Assessment (IRA)Instant Risk Assessment (IRA)
Cost is $165 blood work/$513 UltrasoundCost is $165 blood work/$513 Ultrasound
DS 1:301 (90%) T18/13 1:150 DS 1:301 (90%) T18/13 1:150 (95%)(95%)
““Invasive diagnostic Invasive diagnostic testing for testing for
aneuploidy should be aneuploidy should be available to all available to all
women regardless of women regardless of maternal age”maternal age”
ACOG, December 2007ACOG, December 2007