Comparison of Prenatal Screening Tests for the Detection of Down Syndrome

1
Comparison of Prenatal Screening Tests for the
Detection of Down Syndrome

• Prepared by June C Carroll MD CCFP FCFP
• Sydney G. Frankfort Chair in Family Medicine
• Associate Professor, Department of Family
  Community Medicine
• Mount Sinai Hospital, University of Toronto
• Andrea L Rideout MS, CGC, CCGC
• Certified Genetic Counsellor
• Project Manager The Genetics Education Project
• Funded by Ontario Womens Health Council
• Version February 2006

2
Acknowledgements

• Reviewed by Members of The Genetics
  Education Project Committee
• Funded by The Ontario Women's Health Council
  as part of its funding to The Genetics
  Education Project
• Health care providers must use their own
  clinical judgment in addition to the information
  presented herein. The authors assume no
  responsibility or liability resulting from the
  use of information in this presentation.

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Outline

• Prenatal screening options for chromosome
  disorders - current and new technologies
• Womens information needs
• to facilitate informed choice
• Case examples
• Whats on the horizon in prenatal genetic
  screening?
• Bottom line

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Prenatal (PN) Diagnosis

• 1/300 pregnancies have recognizable chromosomal
  abnormalities
• 95 are Trisomy 21, 18, 13, or changes in X and Y
• Most of these are Down syndrome (DS)
• Increasing maternal age increases risk of
  chromosomal abnormalities

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Risk of DS and Chromosomal Abnormalities at Term
Maternal Age at Delivery (yr) Risk of DS Risk of Any Chromosomal Abnormality
20 1/1650 1/530
25 1/1250 1/480
30 1/950 1/390
35 1/385 1/180
40 1/100 1/65
45 1/30 1/19
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Benefits of Prenatal Screening and Diagnosis

• Parental reassurance (if normal)
• Prenatal diagnosis may allow women to undertake a
  pregnancy they might not have otherwise
  undertaken
• If abnormality detected
• Increased parental options
• further testing
• referral
• counselling re planned birth or termination
• preparation for special needs child
• Altered obstetric management
• Facilitated neonatal management

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Risks of Prenatal Screening and Diagnosis

• Parental anxiety
• False positive
• True positive
• Pregnancy complications
• Pregnancy loss

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Prenatal Screening for Chromosome Abnormalities

• Offer to all pregnant women
• gt90 of structural and chromosomal fetal
  abnormalities are born to low risk women
• Maternal age alone poor screening tool
• Only detects approx 30 of DS cases
• 1996 CTFPHE recommended offering MSS to pregnant
  women

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Prenatal Screening for Chromosome Abnormalities

• Participation variable across Canada
• Physicians routinely offering MSS to all pregnant
  women
• gt85 Ontario family physicians
• 85 Newfoundland family physicians
• 22 Northern Alberta physicians
• 48 uptake of MSS by pregnant women in Ontario
• What are concerns about MSS screening?
• High false positive rate 10 (7DS, 3 NTD,
  0.3 T18)
• Carroll et al CMAJ 1997, Chandra et al J Obstet
  Gynaecol Can 2003, McElligott et al ASHG Poster
  2004, Summers et al J Med Screen 2003.

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Prenatal Screening Options
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Options for Prenatal Screening for DS and trisomy
18

• Integrated Prenatal Screening (IPS)
• Serum Integrated Prenatal Screening (Serum IPS)
• First Trimester Screening (FTS)
• Quadruple maternal serum screening (Quad)
• Maternal serum screening (Triple)
• Diagnostic tests Amniocentesis/CVS
• What is available in your community?

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Integrated Prenatal Screening (IPS)

• 2 step screening combining
• T1 (11-13 6/7 weeks ideally 11)
• Nuchal translucency measurement
• Maternal serum marker
• PAPP-A (pregnancy-associated plasma protein)
• T2 (15-20 weeks ideally 15-17)
• Maternal serum markers
• AFP, uE3, hCG
• Single risk assessment produced in second
  trimester

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Nuchal Translucency (NT)
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Nuchal Translucency

• Subcutaneous fluid-filled space located between
  back of fetal neck and skin
• Measured on U/S between 1113 6/7 weeks,
  measurement is not valid outside of this time
  period
• NT increases with gestational age
• Between 11-13 6/7 weeks gt3.0 or 3.5mm (depending
  on the centre) is considered elevated
• Diagnostic testing indicated
• Fetal echocardiogram indicated 20 weeks (if
  NTgt3mm)
• Detailed anatomy scan at 18-20 weeks
• Genetic counselling

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Nuchal Translucency

• Increased NT associated with
• Trisomies 21, 18, 13, triploidy and Turner
  syndrome
• Spontaneous fetal loss
• With normal chromosomes cardiac defects,
  diaphragmatic hernia, pulmonary defects, skeletal
  dysplasias, congenital infection, metabolic/haem
  disorders, rare single gene disorders
• Normal pregnancy chance of a normal birth
  varies with size of NT measurement
• Nicolaides. Am J Obstet Gynecol 200419145
• Souka et al. Ultrasound Onstet Gyncol 2001189

NT measurement Chance of normal birth
3.4mm 95
3.5 4.4mm 70-86
4.5 5.4mm 50-77
5.5 6.4mm 67
6.5mm 31
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Serum Integrated Prenatal Screening (SIPS)

• Serum only - 2 step approach
• Combines first and second trimester serum markers
  to produce single risk assessment
• T1
• PAPP-A 11-136/7 weeks
• 11 weeks is ideal
• T2
• AFP, uE3, hCG, Inhibin-A 1520 weeks
• 15-17 weeks is ideal
• Consider when NT not available
• False positive rate lower with a dating ultrasound

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First Trimester Screening (FTS)

• NT measurement 11 to 136/7 weeks
• T1 serum markers
• PAPP-A, free beta hCG 11-136/7 weeks
• 11 weeks ideal
• NTD screening with MS-AFP and/or ultrasound is
  still recommended in T2

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Quadruple Screening

• Second trimester maternal serum screening
• 15-20 weeks 15-17 weeks optimal
• AFP, uE3, hCG, Inhibin-A
• Maternal Serum Screening (Triple)
• Same as Quad screening but without Inhibin-A
• False positive rate lower with a dating ultrasound

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Comparison of PN Screening Tests in Detecting
Down Syndrome
Test Detection Rate (DR) False Positive Rate (FPR)
IPS 85 - 90 2 - 4
Serum IPS 80 - 90 2 - 7
FTS 78 - 85 3 - 9
Quad 75 - 85 5 - 10
Triple 60 - 85 5 - 12
NT alone 60 - 70 5
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Prenatal Genetic Screening Tests
Test Pros/Cons
IPS Highest DR, lowest FPR Need reliable NT Must present in T1 Results available in T2 Amniocentesis for diagnostic testing
Serum IPS - Improved DR and FPR compared to MSS Quad Consider for women who present in T1 with NT unavailable Results available in T2 Amniocentesis for diagnostic testing
FTS - Improved DR and FPR compared to MSS Quad Need reliable NT Must present in T1 Results available in T1 (by 15 weeks) CVS for diagnostic testing Does not screen for NTDs remember MSAFP at 15- 20 weeks
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Prenatal Genetic Screening Tests
Test Pros/Cons
Quad screen Improvement on MSS (triple) Consider for women presenting in T2 Consider if IPS, FTS or SIPS not available Amniocentesis for diagnostic testing
Triple screen - Readily available -Amniocentesis for diagnostic testing - High FPR
NT alone Advantage of dating, identifying multiple gestations, and major fetal anomalies Suitable for multiple gestation Low DR
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Comparison of Prenatal Screening Tests
Percent
PPV 1 in 9 1 in 14 1 in 32 1
in 32 1 in 49 1 in 104
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Prenatal Genetic Screening TestsOntario Data
Test DR FPR
IPS gt 90 2-3
Serum IPS 85 4
MSS Triple 71 7
Summers AM et. al J Med Screen 2003
10107-111. Summers AM Personal communication
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Diagnostic Testing

• Chorionic Villus Sampling (CVS)
• Performed at 10-14 weeks
• Highly accurate for chromosome disorders
• Early first trimester
• Not as widely available
• Risk of fetal loss 1-2
• Higher rate of repeat procedures than amnio
• Chance of ambiguous results

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Diagnostic Testing

• Amniocentesis
• Performed from 15-20 weeks (15-17 ideal)
• Results available
• 1-3 weeks later
• Highly accurate
• Risk of fetal loss 0.5-1

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What do women prefer?

• Low false positive rate
• High detection rate
• Timing of results
• Timing of termination

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From the Literature

• A Dutch study of both high risk and low risk
  women found that both groups preferred FTS
• Women were given an information package about
  FTS, second trimester screening and diagnostic
  testing for DS.
• 95 of high risk women preferred first trimester
  screening for Down syndrome to second trimester
  screening.
• 80 of low risk women also preferred first
  trimester screening to second.
• DeGraaf IM et. al 2002 Prenat Diagn 22624-629.

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From the Literature

• A British study of 291 low risk women found that
  the majority of women preferred the IPS option to
  FTS
• The tests were presented in the following
  theoretical situation
• IPS results at 15 wks - 95 DR
• 2 risk of miscarriage after diagnostic testing
• FTS result at 12 wks - 80 DR
• 3 risk of miscarriage after diagnostic testing
• Bishop AJ et. al 2004 BJOG 111 775-779

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Counselling Issues
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The Basics of Counselling

• Pre-test counselling
• Gather information
• Risk assessment
• Patient education
• Identify options engage in dialogue
• Promote autonomous decision-making
• Psychological assessment
• Non-directive

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Patient Education

• Available options
• Difference between screening test and diagnostic
  test
• Benefits and limitations of screening and
  diagnostic testing (if appropriate)
• Option of no testing

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Assist with Decision Making

• Explore values, experiences, beliefs
• Family structure other children, supportive
  partner, extended family, etc.
• Encourage women to consider possibility of
  positive screen result in advance of test
• Think about what they might do in response to
  result

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Assist with Decision Making

• Encourage women to consider the possibility of a
  negative result
• Relieve anxiety?
• Is this information you want to know in advance?
• Knowing in advance allows time to prepare for the
  birth of a special needs child, grieving for the
  loss of a healthy baby and time to adjust
  expectations.

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Psychological Assessment

• Consider
• Patients ability to deal with
• Uncertainty
• Disability
• Risk of miscarriage
• Personal beliefs re option of termination
• If wouldnt consider termination need to
  prepare for birth of affected child

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Non-Directive

• Offer informed choice
• No matter what their moral or religious beliefs
• Beliefs and behaviours may change in face of
  positive screen or amnio/CVS result
• Consider
• Your own beliefs and how they may
• Influence your counselling style
• Differ from your patients beliefs
• Carroll et al. Can Fam Physician 2000 46614

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Cases
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Case 1 - Vanessa

• Age 27
• 8 weeks pregnant
• G2P1
• Previous pregnancy uncomplicated
• Married for 5 years, healthy 3 year old daughter

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Case 1 Vanessa .

• What prenatal genetic screening options would you
  discuss with Vanessa?
• Discuss options with benefits, limitations,
  availability
• New screening tests may require earlier first
  prenatal visit

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Case 1 Vanessa .

• If Vanessa was 38..?
• Could go directly to CVS, amnio
• FTS/IPS more accurate than age
• What might affect her decision?
• Miscarriage rate
• Performance of amnio/CVS compared to IPS, FTS,
  MSS
• May detect problems other than Down syndrome
• Her perception of risk/morbidity associated with
  DS
• Degree of certainty/uncertainty she can tolerate
• Her personal/family/religious beliefs

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Case 2 - Marta

• Age 34
• 17 weeks pregnant
• To discuss result of IPS screen

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Case 2 Marta

• Results

Screening result SCREEN POSITIVE
Reason Increased Risk of Down syndrome
Down syndrome risk 1 in 130 (at term)
Risk of NTD 1 in 7000
Comment Down syndrome risk due to maternal age alone is 1 in 400
COMMENTS AND RECOMMENDATIONS Down syndrome The
risk of Down syndrome is GREATER than the
screening cut-off of 1 in 200 at term. If the
gestational age is confirmed, counselling
regarding the risks and benefits of AMNIOCENTESIS
is suggested.
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Case 2 Marta

• How would you present the results?

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Case 3 - Marie

• 33 years old
• G2P0
• Miscarriage last year
• Trying to get pregnant for several years
• 14 weeks pregnant
• Following U/S for NT for IPS you received
  report from radiologist indicating NT is elevated
  (4.0mm) for this gestational age
• What would be important to discuss with Marie and
  her partner at this time?

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Case 3 Marie.

• Marie was referred for genetic counselling
• Offered
• Complete IPS screening
• Chromosome testing
• Ultrasound 18 - 20 wks echocardiogram 20 - 22
  wks
• Counselled re risk of miscarriage with CVS or
  amnio
• May be even more significant for this couple in
  view of infertility and miscarriage

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Genetic Screening
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Pearls of prenatal genetic screening

• Take a 3 generation family history
• Look for
• Potential patterns of inheritance
• Consanguinity
• Family History of
• birth defects
• mental handicap
• stillbirths or childhood deaths
• chromosome disorders
• severe childhood conditions
• (MD, CF)

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Pearls of prenatal genetic screening

• Pregnancy History
• Maternal age 35
• 3 or more spontaneous abortions
• Stillbirths
• Childhood deaths
• Infertility

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Pearls of prenatal genetic screening

• Consider carrier screening for
• Hemoglobinopathies Mediterranean, African,
  Middle Eastern, Asian, Hispanic/South/Central
  American background
• CBC ? MCV lt80
• Hemoglobin electrophoresis
• Questions? call genetics
• To find a genetics centre near you
• http//www.cagc-accg.ca/centre1.html

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The Ashkenazi Panelprenatal screening

• Ashkenazi Jewish refers to those individuals of
  Eastern European Jewish ancestry.
• Patients may be referred to genetics for
  counselling and screening.

Disease Tests
Tay-Sachs 1 in 30 Biochem Molecular DNA
Canavan 1 in 40 Molecular DNA Test
Familial Dysautonomia 1 in 30 Molecular DNA Test
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Whats new in Prenatal Screening?

• Cystic fibrosis
• CCMG recommends carrier screening to
• Individuals who have a family history of CF
• Does not endorse general population screening
• Low carrier frequency in non-Northern Europeans
• Detection rate low in non-Northern Europeans
• Issue of informed choice
• ACOG/ACMG recommends
• Carrier screening for Caucasians, AJ or couples
  with a family history, planning or currently
  pregnant. Frequency 1 in 25 - 29
• Carrier screening should be available to other
  ethnic groups

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Dont Forget

• Consider referral to genetics for
• Fragile X syndrome, other intellectual
  disabilities
• Deafness
• Muscular dystrophy, myotonic dystropy, spinal
  muscular atrophy
• Gaucher Disease other metabolic diseases
• Achondroplasia, other skeletal dysplasias
• If family history of possible genetic condition
• discussion with or referral to genetics is
  suggested

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Bottom Line

• New screening tests for chromosomal abnormalities
  are available
• Improved DR and FPR
• Earlier timing
• Limited availability
• Women want informed choice
• Genetic centres welcome inquiry and referral
• If in doubt about whether GT is available - ask

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Common Questions
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Question 1

• My patient is 40 years old. What is the value of
  screening tests for Down syndrome verses going
  straight to diagnostic testing?
• For those women who want to know for certain if
  their fetus is affected with Down syndrome -
  diagnostic testing is more accurate and may offer
  them peace of mind that a screening test cannot.
• Diagnostic testing has an increased risk of
  miscarriage
• May be a significant factor for older women to
  consider
• Screening tests for Down syndrome will detect a
  minimum of 75 (Quad screening) to 90 (IPS) of
  Down syndrome cases

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Question 2

• My patient is 18 years old. Why bother with
  screening tests for Down syndrome when her age
  related risk is so low?
• Although a womans risk of having a child with
  Down syndrome increases with age screening for
  Down syndrome by age alone will only detect 30
  of Down syndrome cases.
• Because more younger women have children, more
  children with DS are born to this age group of
  mothers.
• Prenatal screening tests give a woman her
  individual risk of having a fetus with DS in this
  pregnancy.
• Every woman should be given the opportunity to
  make an informed choice about prenatal screening.

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Question 3

• I have a number of patients who would not end a
  pregnancy affected with Down syndrome Is
  prenatal screening of value for these patients?
• Screening provides information.
• Some women may want to know if their fetus is
  affected with Down syndrome before birth in order
  to plan for the birth of an affected child.
• Other women prefer to wait until birth and do
  not want any information before hand.

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Question 4

• Some of my patients are interested in diagnostic
  testing but are concerned about the risk of
  miscarriage.
• The risk of having a live born baby with any
  chromosome problem at 35 years of age is 1 in
  180.
• When women are offered diagnostic tests, the risk
  of miscarriage (1-2 in 200) is usually smaller
  than their risk of having a baby with a
  chromosome problem.
• The cutoff value for screen positive for each
  screening test (when a woman would be offered
  diagnostic testing) is usually greater than the
  risk of miscarriage from amnio/CVS.

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The Genetics Education Project Committee

• June Carroll MD CCFP
• Judith Allanson MD FRCP FRCP(C) FCCMG FABMG
• Sean Blaine MD CCFP
• Mary Jane Esplen PhD RN
• Sandra Farrell MD FRCPC FCCMG
• Judy Fiddes
• Gail Graham MD FRCPC FCCMG
• Jennifer MacKenzie MD FRCPC FAAP FCCMG

• Wendy Meschino MD FRCPC FCCMG
• Joanne Miyazaki
• Andrea Rideout MS CGC CCGC
• Cheryl Shuman MS CGC
• Anne Summers MD FCCMG FRCPC
• Sherry Taylor PhD FCCMG
• Brenda Wilson BSc, MB ChB, MSc, MRCP(UK), FFPH

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References

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3. American College of Obstetrics Gynecology. ACOG
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   risks to the fetus Number 189, November 1997. Int
   J Obstet Gynaecol 1997 59271-272.
4. American College of Medical Genetics. Statement
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   paternal age. Bethesda Maryland ACMG1996.

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References

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• http//www.fetalmedicine.com/f-downs.htm

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