new strategies in genetic screening for pregnancy
TRANSCRIPT
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New Strategies for Genetic Screening in Pregnancy
Rita W. DriggersCDR MC USN1 June 2009
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Maternal Serum Screening
Goal Identify as many abnormal fetuses
possible (high detection rate) Minimize number of normal pregnancies
with abnormal test result (false positives) Abnormalities identified
Number of chromosomes (aneuploidy) Structural birth defects
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Maternal Serum Screening
Maternal age First recognized screening test Detects only 20% of trisomy 21 cases
Maternal serum alpha-fetoprotein (MSAFP) Late 1970’s - association between high
MSAFP and open neural tube defects 1980’s - association between low MSAFP and
trisomy 21 Increased sensitivity of trisomy 21 detection
to 42%
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Maternal Serum Screening
HCG Late 1980’s - high HCG associated with
trisomy 21 Combined with maternal age and MSAFP,
increased trisomy 21 detection rate to 67% Unconjugated estriol (uE3)
1988 - data published on low uE3 Triple screen (MSAFP, HCG, and uE3)
increased trisomy 21 detection rate to 70%
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Maternal Serum Screening
Inhibin A 1990’s – recognized to be elevated with
trisomy 21 Addition of inhibin A to triple screen (the
quad screen) improved trisomy 21 detection rate to 80%
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Maternal Serum Screening
Quad screen profile in Trisomy 21 MSAFP = 0.74 MoM hCG = 2.06 MoM uE3 = 0.75 MoM Inhibin A = 1.77 MoM
Quad screen profile in Trisomy 18 AFP, HCG, and uE3 levels all reduced Inhibin A not used
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Maternal Age Counseling
Increasing age associated with increased risk of the baby having abnormalities in number of chromosomes
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What are chromosomes?
Packaging for genetic (inherited) information in a cell Chromosomes are like filing cabinet
drawers packed with pieces of paper, where each piece of paper is a gene
Each chromosome is in a pair, one of which comes from mother and the other from father
The number and shape of the chromosomes are critically important
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Chromosome abnormalities
Having an extra chromosome or a missing chromosome means the body has too much or too little genetic information
If the baby has an extra one of the very big or gene rich chromosomes, there is usually a very early miscarriage
Pregnancies which have extra chromosomes 21, 13, or 18 may have live born babies who have serious problems
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Extra chromosome 21--Down syndrome
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Extra chromosome 18—Trisomy 18
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What can be done to test for chromosome abnormalities?
Screening tests 1st trimester 2nd trimester
Diagnostic tests 1st trimester 2nd trimester
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What is quad screen testing?
A blood test done between 14-20 weeks gestation
It measures four proteins found in your blood which actually are passed from the baby or the placenta into your blood stream Alpha fetoprotein (AFP) Human chorionic gonadotropin (HCG) Unconjugated estriol (uE3) Inhibin A
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What do the results mean?
Quad screen gives three pieces of information Risk for baby to have an open spine Risk for baby to have an extra chromosome 18 Risk for baby to have an extra chromosome 21
Given in a number: Ex: 1/400, 1/1000 If greater than risk for a woman age 35 to have a
baby with Down syndrome or Trisomy 21 (1/270), the test is called positive
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Can the test say exactly what my baby has?
No! It can only say whether you have a
higher or lower risk of the problem than was originally thought
IT IS NOT AN EXACT TEST!
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Does the quad screen test find all babies with the problems?
The quad screen will identify 90-100% of babies with open spines or
brains 75% of babies with openings in the
abdomen 81% of babies with Down syndrome
It can miss some babies with Down syndrome
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Does the quad screen test look for all types of abnormalities?
No Only identifies babies with open
spines or abdomens, trisomy 18, or trisomy 21
It is not designed to identify babies with heart, kidney, or arm or leg problems
It cannot identify all kinds of mental retardation
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Do I have to have a quad screen?
No, it is your choice 95% of mothers will have a normal
test and may feel reassured about their pregnancy
5% will have a positive test and will need some additional evaluation Of those who are positive, only 1 in 20
will in fact have a baby with Down syndrome
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You receive the following quad screen results for a 41 yo G2P1
Screen POSITIVE for Down Syndrome Quad screen ONTD Risk <1:5000 Age Risk Down Syndrome 1:76 Quad screen Down Risk 1:265 Quad screen Trisomy 18 Risk 1:1663
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What happens if my test is positive?
Test may be positive because dates are wrong Test done between 14-20 weeks Usually first ultrasound is used to date
your pregnancy If you haven’t had an ultrasound, your
test may be corrected just by doing an ultrasound and correcting your dates
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What if my test is positive and my dates are correct?
The next step is to do a detailed ultrasound (called a targeted or level II) to look at the baby The ultrasound can pick up over 95% of
all problems with the baby’s spine or abdomen
It can also look for other abnormalities or changes in the baby which might suggest a greater chance of Down syndrome or Trisomy 18
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What are ultrasound markers?
Early 1990’s - “genetic ultrasound” Sonographic markers for aneuploidy
Short humerus Short femur Pyelectasis Echogenic bowel Echogenic intracardiac focus Nuchal thickening
Addition genetic US quad screen increases trisomy 21 detection rate to 90%
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Does the ultrasound give 100% answers?
No The ultrasound needs to be done by
an experienced person who has a good ultrasound machine If no problems are seen in the detailed
ultrasound the chance for the baby to have a birth defect is reduced, but not zero
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Who needs a 100% answer?
Some people need to have as much information as possible about their babies because that information may influence what they would do in their pregnancy
Some people need to know for planning purposes
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How to get a 100% answer
A test called an amniocentesis can be offered Takes small sample of fluid from
around the baby by passing a thin needle through the mother’s abdomen into the sac around the baby
The fluid has some of baby’s cells in it, so the baby’s chromosomes can be counted
Proteins in the fluid which suggest an open spine can also be measured
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Is that a risky test? Amniocentesis is a very safe test and
has been done for over 50 years 15-20 weeks Earlier amniocentesis results in
significantly higher rates of pregnancy loss and complications
Procedure-related loss rate at 15-20 weeks as low as 1 in 300–500 May be even lower with experienced
individuals or centers
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Prenatal Diagnosis of Aneuploidy
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Prenatal Diagnosis of Aneuploidy
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Is the amniocentesis reliable?
Yes If it says there is no problem, there
is no problem If it says the baby has a
chromosome problem, then there is truly a problem
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Do I have to have an amniocentesis?
No It is only offered as a way to get the
most possible information about the baby
Not everyone wants or needs that information
If you didn’t want an amniocentesis, you would still get the same careful prenatal care
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Nuchal translucency
Mid-1990’s - strong association between size fluid collection at back fetal neck in 1st trimester, “nuchal translucency,” and risk of trisomy 21
Increased NT now recognized as early presenting feature of broad range of fetal chromosomal, genetic, and structural abnormalities
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Nuchal TranslucencyNuchal Translucency
www.mums.me.uk/nuchal.htm
Dr Eva Pajkrt, University of Amsterdam
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Normal Nuchal Translucency MeasurementNormal Nuchal Translucency Measurement
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Increased Nuchal Translucency Increased Nuchal Translucency Measurement Measurement
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1st Trimester Aneuploidy Screening
Around this same time period 1st trimester analytes recognized Free -HCG elevated to 1.98MoM Pregnancy-associated plasma protein A
(PAPP-A) reduced to 0.43MoM Used alone, 1st trimester serum
analytes detect 65% of trisomy 21 Combined with NT, 82-87% of trisomy
21 fetuses detected
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Should I get the first trimester test or the quad screen?
Advantage of 1st trimester screening Women who present before 14 wks have
information sooner Can be offered genetic counseling and
chorionic villus sampling (CVS)
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What is CVS?
CVS Placental villi obtained through a
transcervical or transabdominal approach
Performed after 9 completed weeks - 13th weeks
Primary advantage over amniocentesis is earlier results
Earlier reassurance for when results normal Allow for earlier and safer methods of
pregnancy termination when results are abnormal
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Is CVS riskier than amniocentesis?
Overall pregnancy loss rate after CVS is greater than after amniocentesis increased background rate of
spontaneous pregnancy loss 9-16 weeks In experienced hands, the CVS loss
rate appears to approach rate for midtrimester amniocentesis
No difference in loss rates after transcervical or transabdominal CVS
Transverse limb deficiencies more common performed before 9 weeks
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What are the complications from CVS?
Other CVS complications Vaginal spotting or bleeding
in up to 32.2% of transcervical CVS patients Culture failure, amniotic fluid leakage, and
infection (< 0.5%) Chromosomal mosaicism (1%)
amniocentesis performed at 15-20 weeks to assess whether mosaicism is present in amniocytes
amniocentesis result usually normal, and the mosaicism is assumed to be confined to the trophoblast
unlikely to cause defects but may result in 3rd trimester growth restriction
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Prenatal Diagnosis of Aneuploidy
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What tests should be done after 1st trimester screening or CVS?
1st trimester screening does not include MSAFP Neural tube defect screening by 2nd-tri
MSAFP screening or US NT > 3.5 mm with negative result on
aneuploidy screen, normal fetal chromosomes, or both, at risk for Nonchromosomal anomalies Congenital heart defects Abdominal wall defects Diaphragmatic hernias Genetic syndromes
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Can other information be gained from 1st trimester screening?
Abnormal 1st-trimester serum markers or increased NT may also increased risk for adverse pregnancy outcome Fetal loss before 24 weeks IUFD IUGR Preterm birth
NT > 3.5 mm should be offered: Targeted ultrasound examination Fetal echocardiogram Genetic counseling
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Aneuploidy Screening
Test Trisomy 21 Detection Rate
FPR
Triple screen 70% 5%
Quad screen 81% 5%
Quad + genetic US 90% 3.1%
NT alone 64-70% 5%
PAPP-A + free -HCG 65% 5%
NT + PAPP-A + HCG 82-87%* 5%
*87% at 11 wks, 85% at 12 wks, 82% at 13 wks
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Aneuploidy Screening
ACOG recommendations (Jan 2007) All women be offered aneuploidy screening,
regardless of age A strategy which incorporates both 1st and
2nd trimester screening be offered to women who present in the 1st trimester
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Prenatal Diagnosis of Aneuploidy
Criteria for invasive testing traditionally maternal age ACOG Practice Bulletin (December 2007)
“Invasive diagnostic testing for aneuploidy should be available to all women, regardless of maternal age.”
Many factors influence a woman’s decision Risk fetus will have a chromosomal abnormality Risk of pregnancy loss from procedure Consequences of having an affected child
Recent studies suggest lower loss rates Older studies performed prior to concurrent use of high-resolution US
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Aneuploidy Screening
Screening method
Trisomy 21
detection
FPR Comments
Serum Integrated
85-88%* 5% No 1st tri detection, no NT100% get 2nd tri screen
Integrated 94-96%* 5% No 1st tri detection, with NT 100% get 2nd tri screen
Sequential 95%* 5% 2% require CVS
98% get 2nd tri screen
Contingent 88-94%* 4% 2% require CVSOnly 22% get 2nd tri screen
3% require amnio
*Best when 1st trimester screen at 11 wks
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Aneuploidy Screening
So which screening test(s) should be offered?!!
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Aneuploidy Screening
Before deciding which strategy or strategies to offer your patients Identify tests available in your area Determine which strategy or strategies will
best meet your needs and the needs of your patients
Women first seen during 2nd trimester Options limited to quad screen and genetic
ultrasound
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Aneuploidy Screening
Women who present in the 1st trimester Strategy incorporating both 1st and 2nd
trimester screening should be offered If CVS is not available
Offer integrated screening to patients who present in 1st trimester in order to take advantage of improved detection rate and low false-positive rate
Offer 2nd trimester screening to patients who present after 13-6/7 weeks
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Aneuploidy Screening
If NT measurement is not available or cannot be obtained in an individual Offer serum integrated screening to patients
who present early and 2nd trimester screening to those who present later
Counsel about screening strategy or strategies used Detection rates False-positive rates
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Aneuploidy Screening
Reporting results to patients Provide numerical risk (rather than
positive versus negative) Contrast this risk with general population
risk and age-related risk
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Summary
1st and 2nd trimester screening tests for fetal chromosomal abnormalities, correct timing for, and associated sensitivities of these tests
Options for screening tests that combine 1st and 2nd trimester results
Options for 1st and 2nd trimester prenatal diagnosis of aneuploidy, correct timing and associated loss rates
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Questions???