First and Second Trimester Genetic Screening. Objectives. Genetic (chromosome) Testing

First and Second Trimester Genetic Screening Patricia O’Day, MD Maternal-Fetal Medicine Essential Health – Duluth Objectives     Review the d...
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First and Second Trimester Genetic Screening Patricia O’Day, MD Maternal-Fetal Medicine Essential 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


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 

Early complications ROM bleeding fetal loss

11-14 wk 2.9% 1.9% 2.2%

16-19 wk 0.2% 0.2% 0.2%

No difference in late complications Brumfield et al, Obstet Gynecol, 1996; 88(1):114-8


1st Trimester Invasive Testing CEMAT

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 Testing NICHD 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 midtrimester 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


Genetic screening     

Age Triple screen Quad screen First trimester screening Ultrasound

Genetic screening Age

 

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

Genetic Screening 2nd Trimester  

 

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 screening 2nd 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


First Trimester Nuchal Measurements 

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


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

First Trimester Screening (BUN Study)

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

1st and 2nd Trimester Comparisons SURUSS 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


1st and 2nd Trimester Comparisons SURUSS Trial

For an 85% Trisomy 21 detection rate: 

1st trimester screen (NT, hCG, PAPP-A)

Quad screen (FP, uE3, hCG, inhibin-A)

“Integrated screen” (NT,PAPP-A + quad)

4.3% false positive rate 6.2% false positive rate 0.9% false positive rate

1st and 2nd Trimester Comparisons FASTER Trial

Prospective trial 38,167 patients, 117 w/ trisomy 21 1st trimester combined screen

2nd trimester quad screen

1st trimester results not disclosed

 

NT, PAPP-A, free hCG FP, total hCG, uE3, inhibin-A

Malone et al, NEJM; 2005; 353(19): 2001-11

1st and 2nd Trimester Comparisons FASTER 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% 


Step-wise Sequential Screening FASTER Trial

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

Fully Integrated Screening FASTER 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 Screening Details 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


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 MSFP Do the MSFP at ~16-20 wks Order MSFP only (not the quad screen)


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


Septated Cystic Hygroma 

Incidence of 1 in 285 screened patients 51% of fetuses had chromosome abnormality

34% had major structural abnormality

 

Trisomy 18 or 21 or Turner syndrome in 85% Cardiac or skeletal

8% fetal demise 17% survival with normal pediatric outcome Malone et al, Obstet Gynecol 2005; 106:288-94

First Trimester Screening ACOG 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


First Trimester Nuchal Measurements 

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 FetalMedicine Foundation *ACOG committee opinion; July 2004

First Trimester Screening ACOG 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

First Trimester Diagnosis Where Are We Going

 

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


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