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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