First and Second Trimester Genetic...
Transcript of First and Second Trimester Genetic...
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First and Second Trimester Genetic Screening
Patricia O’Day, MDMaternal-Fetal MedicineEssential Health – Duluth
Objectives
Review the difference between genetic diagnosis and screening
Review the history and evolution of genetic screening in pregnancy
Explain the different options available for first and second trimester genetic screening
Effectively counsel patients as to the options available and the associated detection rates
Genetic (chromosome) Testing
Diagnosis vs. screening Hard concepts for some patients to
understand Validity of screening depends on
prevalence in the population
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Genetic diagnosis
CVS Amniocentesis Fetal blood
Genetic diagnosis
All methods of prenatal diagnosis are invasive
CVS gives earliest diagnosis (10-13 wks) if pts would consider TOP, this affords
earlier and safer procedures
Amniocentesis is 15 weeks and beyond
1st Trimester Invasive Testing
0.2%2.2%fetal loss0.2%1.9%bleeding0.2%2.9%ROM
16-19 wk11-14 wk
Early complications
No difference in late complications
Brumfield et al, Obstet Gynecol, 1996; 88(1):114-8
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1st Trimester Invasive TestingCEMAT
Losses between amnio and 20 wks: Early amnio: 53/1916 (2.8%) Mid amnio: 9/1775 (0.5%)
Also with early amnio More failed procedures, multiple sticks,
fluid leakage, failed cultures, and talipes equinovares
Johnson et al, Prenat Diagn, 1999; 19(8):732-8
1st Trimester Invasive TestingNICHD EATA Trial
Randomized trial comparing amnio to transabdominal CVS at 11+0 to 14+6 wks over 90% done after 13 wks
Spontaneous losses and procedure related terminations 1.5% with amnio, 0.9% with CVS (RR = 1.74)
4-fold increase in rate of talipes equinovares after amniocentesis
Philip et al, Obstet Gynecol 2004; 103(6):1164-73
Invasive Testing
More recent studies demonstrate mid-trimester amnio complication rate of 1:400 to 1:600
Early amnio is not a reasonable alternative Increased complications, talipes
CVS carries a slightly higher risk than amnio
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Genetic screening
Age Triple screen Quad screen First trimester screening Ultrasound
Genetic screeningAge
Standard of care for prenatal screening until 20 years ago was age and family history
Screen “positive” were pts ≥ age 35 20% detection rate, 5% false positive
rate
First advance was the triple screen Combined -hCG, uE3, FP with age in
women under 35, age only screening over age 35
65% detection rate, 10% false positive rate All women over 35 were screen positive,
3-5% under 35 were screen positive
Genetic Screening2nd Trimester
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Genetic screening2nd Trimester
Quad screen was then offered in some labs
Inhibin is added to other three serum markers
This increases detection to ~80%, with a 5% FP rate
First Trimester Screening
Next interest was in moving screening to the first trimester
Motivated by desire to give earlier results
Both ultrasound and serum markers were investigated
First Trimester Serum Screening
Rates of detection of trisomy 21 for serum markers: 17% for FP, 4% for estriol, 29% for hCG, 42% for PAPP-A
Combination of PAPP-A, hCG and maternal age: detection rate was 63%
Haddow, N Engl J Med 1998;338:955–61
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First Trimester NuchalMeasurements
Assessment of risk by a combination of maternal age and fetal nuchal-translucency, over 96,000 subjects Measured by ultrasound at 10-14 weeks of
gestation Abnormal nuchal in:
8.3% of normal pregnancies 82% with trisomy 21 78% with other chromosome defects
Snijders RJ et al; Lancet 1998
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First Trimester Screening (BUN Study)
Maternal serum assayed for free beta-HCG and PAPP-A, ultrasound measurement of nuchal translucency
78.7% detection rate for trisomy 21, FP rate of 5%
Identified 90.9% of trisomy 18 with a 2% FP rate
Wapner et al NEJM Vol 349:1405-1413: 2003
Measurements of nuchal translucency were assessed according to the standards of the Fetal Medicine Foundation of London
Sonographers underwent training and certification before participating in the study
First Trimester Screening (BUN Study)
1st and 2nd Trimester ComparisonsSURUSS Trial
Prospective study 47,053 singleton pregnancies
101 with trisomy 21 Nuchal translucency measurements Serum and urine samples in 1st and 2nd
trimester 1st trimester results not disclosed to patient
Wald et al, J Med Screen 2003; 10:56-104
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For an 85% Trisomy 21 detection rate: 1st trimester screen (NT, hCG, PAPP-A)
4.3% false positive rate
Quad screen (FP, uE3, hCG, inhibin-A) 6.2% false positive rate
“Integrated screen” (NT,PAPP-A + quad) 0.9% false positive rate
1st and 2nd Trimester ComparisonsSURUSS Trial
Prospective trial 38,167 patients, 117 w/ trisomy 21 1st trimester combined screen
NT, PAPP-A, free hCG 2nd trimester quad screen
FP, total hCG, uE3, inhibin-A 1st trimester results not disclosed
Malone et al, NEJM; 2005; 353(19): 2001-11
1st and 2nd Trimester ComparisonsFASTER Trial
1st and 2nd Trimester ComparisonsFASTER Trial
Trisomy 21 detection rate (5% FP): 1st tri combined screen: 85-87% (11-12 wks)
2nd tri quad screen: 81% Stepwise sequential screening: 95% Fully integrated screening: 96%
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1st trimester combined screen Positive results – offer CVS Negative results – quad screen at 15 wks
New risk estimate provided that combines results of 1st and 2nd trimester markers Offer amnio if this new result is positive
Must send all tests to the same lab
Step-wise Sequential ScreeningFASTER Trial
Fully Integrated ScreeningFASTER Trial
1st trimester NT and PAPP-A Results not disclosed
2nd trimester quad screen Assessment of risk then calculated Amnio offered if screen positive
1st Trimester Genetic ScreeningDetails of Testing
CRL between 45 - 84 mm Corresponds approximately to 11 – 13+6 wks
“Normal” nuchal measurement directly proportional to CRL
Risk assessment based on MoM for NT, hCG, PAPP-A and maternal age
Report will give numeric risk (1:230) Report as “normal” if risk is less than that of a 35 y/o
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Important Reminder
1st trimester screening does not evaluate for open NTDs or abdominal wall defects
All patients who choose 1st trimester testing must be offered a MSFP
Do the MSFP at ~16-20 wks Order MSFP only (not the quad screen)
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Abnormal Nuchal Measurement
29,154 pregnancies; 1822 had abnormal nuchal
All had normal chromosomes 50 cases with heart defects
28 (56%) had abnormal nuchal Abnormal nuchal measurement identifies
many fetuses with heart defects
Hyett et al BMJ 1999;318:81-85
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Septated Cystic Hygroma
Incidence of 1 in 285 screened patients 51% of fetuses had chromosome abnormality
Trisomy 18 or 21 or Turner syndrome in 85%
34% had major structural abnormality Cardiac or skeletal
8% fetal demise 17% survival with normal pediatric outcome
Malone et al, Obstet Gynecol 2005; 106:288-94
First Trimester ScreeningACOG Opinion
First-trimester screening using nuchal translucency, free ß-hCG, and PAPP-A has comparable detection rates and positive screening rates for Down syndrome as second-trimester screening using 4 serum markers
ACOG committee opinion; July 2004
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First Trimester NuchalMeasurements
ACOG bulletin wording about reliability*: The ability to measure nuchal translucency reliably is dependent
on the operator, ultrasound equipment, proper magnification and contrast, fetal position, correct placement of the calipers,and maternal body habitus
Ultrasonographer training and ongoing quality assurance are essential
At present, labs will not process specimens sent from non-certified sonographers
Certification is through the SMFM or London based Fetal-Medicine Foundation
*ACOG committee opinion; July 2004
First Trimester ScreeningACOG Statement
First trimester screening for Down syndrome and trisomy 18 should be offered only if the following criteria can be met: Appropriate ultrasound training and ongoing
quality monitoring programs are in place Sufficient information and resources to provide
counseling regarding the different screening options
Access to an appropriate diagnostic test when screening test results are positive
Goal is definitive noninvasive diagnosis Direct assessment of karyotype
Not deductions from ultrasound or blood
Intact fetal cells in maternal blood Cell-free DNA in maternal blood Fetal trophoblasts from maternal cervix
First Trimester DiagnosisWhere Are We Going