New Strategies for Genetic Screening in Pregnancy

Rita W. DriggersCDR MC USN1 June 2009

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

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%

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%

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%

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

Maternal Age Counseling

Increasing age associated with increased risk of the baby having abnormalities in number of chromosomes

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

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

Extra chromosome 21--Down syndrome

Extra chromosome 18—Trisomy 18

What can be done to test for chromosome abnormalities?

Screening tests 1st trimester 2nd trimester

Diagnostic tests 1st trimester 2nd trimester

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

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

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!

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

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

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

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

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

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

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%

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

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

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

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

Prenatal Diagnosis of Aneuploidy

Prenatal Diagnosis of Aneuploidy

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

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

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

Nuchal TranslucencyNuchal Translucency

www.mums.me.uk/nuchal.htm

Dr Eva Pajkrt, University of Amsterdam

Normal Nuchal Translucency MeasurementNormal Nuchal Translucency Measurement

Increased Nuchal Translucency Increased Nuchal Translucency Measurement Measurement

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

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)

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

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

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

Prenatal Diagnosis of Aneuploidy

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

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

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

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

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

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

Aneuploidy Screening

So which screening test(s) should be offered?!!

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

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

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

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

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

Questions???