The Genetics Education Project Comparison of Prenatal Screening Tests for the Detection of Down Syndrome Prepared by:June C Carroll MD CCFP FCFP Sydney

The Genetics Education ProjectThe Genetics Education Project

Comparison of Prenatal Screening Tests for the

Detection of Down SyndromePrepared 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, CCGCCertified Genetic Counsellor

Project Manager – The Genetics Education Project

Funded by: Ontario Women’s Health Council

Version: February 2006


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.


Outline

Prenatal screening options for chromosome disorders - current and new technologies

Women’s information needs – to facilitate informed choice

Case examples What’s on the horizon in prenatal genetic

screening? Bottom line


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


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


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


Risks of Prenatal Screening and Diagnosis

Parental anxiety

– False positive

– True positive Pregnancy complications Pregnancy loss


Prenatal Screening for Chromosome Abnormalities

Offer to all pregnant women– >90% of structural and chromosomal fetal

abnormalities are born to low risk women

– Maternal age alone poor screening toolOnly detects approx 30% of DS cases

– 1996 CTFPHE recommended offering MSS to pregnant women


Prenatal Screening for Chromosome Abnormalities

Participation variable across Canada– Physicians routinely offering MSS to all pregnant

women: >85% 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% (7%DS, 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.


Prenatal Screening Options


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?


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


Nuchal Translucency (NT)


Nuchal Translucency Subcutaneous fluid-filled space located between back of

fetal neck and skin Measured on U/S between 11–13+ 6/7 weeks,

measurement is not valid outside of this time period NT increases with gestational age Between 11-13+ 6/7 weeks >3.0 or 3.5mm (depending

on the centre) is considered elevated– Diagnostic testing indicated

– Fetal echocardiogram indicated ~20 weeks (if NT>3mm)

– Detailed anatomy scan at 18-20 weeks

– Genetic counselling


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 2004;191:45 Souka et al. Ultrasound Onstet Gyncol 2001;18:9

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%


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: 11-13+6/7 weeks

11 weeks is ideal

T2– AFP, uE3, hCG, Inhibin-A: 15–20 weeks

15-17 weeks is ideal

Consider when NT not available

False positive rate lower with a dating ultrasound


First Trimester Screening (FTS)

NT measurement: 11 to 13+6/7 weeks T1 serum markers

– PAPP-A, free beta hCG: 11-13+6/7 weeks 11 weeks ideal

NTD screening with MS-AFP and/or ultrasound is still recommended in T2


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


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%


Prenatal Genetic Screening TestsTest Pros/Cons

IPS - Highest DR, lowest FPR- Need reliable NT- Must present in T1- Results available in T2- Amniocentesis for diagnostic testing

SerumIPS

- 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


Prenatal Genetic Screening Tests

Test Pros/Cons

Quadscreen

- Improvement on MSS (triple)- Consider for women presenting in T2 - Consider if IPS, FTS or SIPS not available-Amniocentesis for diagnostic testing

Triplescreen

- 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


Comparison of Prenatal Screening Tests

0

10

20

30

40

50

60

70

80

90

IPS SIPS FTS Quad Triple NT

DR

FPR

PPV: 1 in 9 1 in 14 1 in 32 1 in 32 1 in 49 1 in 104

Percent

%


Prenatal Genetic Screening TestsOntario Data

Test DR FPR

*IPS > 90% 2-3%

*Serum IPS 85% 4%

**MSSTriple

71% 7%

** Summers AM et. al J Med Screen 2003 10:107-111.

* Summers AM Personal communication


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


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%


What do women prefer?

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


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 22:624-629.


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



Counselling Issues


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


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


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


…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.


Psychological Assessment Consider:

– Patient’s ability to deal with: Uncertainty Disability Risk of miscarriage

– Personal beliefs re option of termination

– If wouldn’t consider termination – need to prepare for birth of affected child


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 patient’s beliefs

Carroll et al. Can Fam Physician 2000; 46:614


Cases


Case 1 - Vanessa

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

daughter


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


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…


Case 2 - Marta

Age 34 17 weeks pregnant To discuss result of IPS screen


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.


Case 2 – Marta… How would you present the results?


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?


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


Genetic Screening


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)


…Pearls of prenatal genetic screening

Pregnancy History:

Maternal age ≥ 35 3 or more spontaneous

abortions Stillbirths Childhood deaths Infertility


…Pearls of prenatal genetic screening

Consider carrier screening for: Hemoglobinopathies – Mediterranean, African, Middle

Eastern, Asian, Hispanic/South/Central American background– CBC → MCV <80

– Hemoglobin electrophoresis Questions? – call genetics

– To find a genetics centre near you:

http://www.cagc-accg.ca/centre1.html


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


What’s 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


Don’t 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


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


Common Questions


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


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 woman’s 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.


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.


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.


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


References1. Jones, KL ed. Smith’s Recognizable Patterns of Human

Malformation 5th ed. W.B. Saunders Company, Philadelphia 1997 pgs: 8-23,30-33,70-87.

2. Cassidy SB, Allanson JE (eds.). Management of genetic syndromes. Wiley-Liss Toronto 2001. pgs:103-129, 195-206, 417-436, 459-484.

3. American College of Obstetrics & Gynecology. ACOG Committee on Genetics Advanced paternal age: risks to the fetus Number 189, November 1997. Int J Obstet Gynaecol 1997; 59:271-272.

4. American College of Medical Genetics. Statement on guidance for genetic counseling in advanced paternal age. Bethesda Maryland: ACMG1996.


References

5. Hook EB, Cross PK, Schreinemachers DM. Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA 1983; 249:2034-2038.

6. Dick PT. and the Canadian Task Force on the Periodic Health Examination. Periodic health examination, 1996 update: 1. Prenatal screening for and diagnosis of Down syndrome. CMAJ 1996; 154:465-479.

7. Carroll JC, Reid AJ, Woodward CA, Permaul-Woods JA, Domb S, Ryan G, Arbitman S, Fallis B, Kilthei J. Ontario Maternal Serum Screening Program: practices, knowledge and opinions of health care providers. CMAJ 1997; 156:775-84.


References

8. Chandra S, Crane J, Hutchens D, Bennett K, O'Grady T, Duff A, MacGregor D. Maternal serum screening: practice patterns of physicians in Newfoundland. J Obstet Gynaecol Can 2003; 25(10):825-829.

9. McElligott KS, Christian SM, Kieffer SA, Reeve J, Bamforth F, Bamforth JS. Maternal serum screening in Northern Alberta: the need for a provincial program. Poster presentation. 2004. Toronto, American Society of Human Genetics Meeting.

10. Summers A, Farrell SA, Huang T, Meier C, Wyatt PR. Maternal serum screening in Ontario using the triple marker test. J Med Screen. 2003; 10:107-111.

11. http://www.fetalmedicine.com/f-downs.htm


References

12. Cheng, C-C, Bahado-Singh RO, Chen S-C Tsai M-S. Pregnancy outcomes with increased nuchal translucency after routine Down syndrome screening. Int J Gynaecol Obstet 2003; 84: 5-9.

13. Malone FD, D’Alton ME. First trimester sonographic screening for Down syndrome. Obstet Gynecol. 2003; 102:1066-1079.

14. Makrydimas G, Sotiriadis A, Ioannidis JAP. Screening performance of first-trimester nuchal translucency for major cardiac defects: a meta-analysis. Am J Obstet Gynecol 2003;189:1330-5.


References

15. Souka AP, Krampl E, Bakais S, Heath V, Nicolaides KH. Outcome of pregnancy in chromosomally normal fetuses with increased nuchal translucency in the first trimester. Ultrasound Obstet Gynecol 2001;18:9-17

16. Nicolaides KH Nuchal translucency and other first-trimester sonographic markers of chromosome abnormalities. Am J Obstet Gynecol 2004;191:45-67.


References

17. Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Dukes K, Bianchi DW, Rudnicka AR, Hackshaw AK, Lambert-Messerlian G, Wald NJ, D'Alton ME; First- and Second-Trimester Evaluation of Risk (FASTER) Research Consortium. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med. 2005; 353:2001-11.

18. Schuchter K, Hafner E, Stangl G, Metzenbauer M, Höfinger D, Philipp K The first trimester 'combined test' for the detection of Down syndrome pregnancies in 4039 unselected pregnancies. Prenat Diagn 2002; 22:211‑215.

19. Wald NJ, Huttly W, Hackshaw AK. Antenatal screening for Down's syndrome with the quadruple test. Lancet 2003; 36:835‑836.


References

20. Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). J Med Screen 2003; 10:56‑104.

21. Wapner R, Thom E, Simpson JL, Pergament E, Silver R, Filkins K, Platt L, Mahoney M, Johnson A, Hogge WA, Wilson RD, Mohide P, Hershey D, Krantz D, Zachary J, Snijders R, Greene N, Sabbagha R, MacGregor S, Hill L, Gagnon A, Hallahan T, Jackson L. for the First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening Group (BUN) Study Group. First‑trimester screening for trisomies 21 and 18. N Engl J Med 2003; 349(15):1405‑1413.


References22. Reference for picture:

http://wchs.health.wa.gov.au/health/c/cvs.htm

23. de Graaf IM, Tijmstra T, Bleker OP, van Lith JMM. Womens’ preference in Down syndrome screening. Prenat Diagn 2002; 22: 624-629.

24. Bishop AJ, Marteau TM, Armstrong D, Chitty LS, Longworth L, Buxton MJ, Berlin C. Women and health care professionals’ preferences for Down’s syndrome screening tests: a conjoint analysis study. 2004 BJOG 111: 775-779.

25. Carroll JC, Brown JB, Reid AJ, Pugh P. Women’s experience of maternal serum screening. Can Fam Physician 2000; 46:614-620


References26. Ray JG, Meier C, Vermeulen MJ, Boss S, Wyatt PR, Cole

DE. Association of neural tube defects and folic acid food fortification in Canada. Lancet 2002; 360:2047-2048.

27. Bennett RL, Motulsky AG, Bittles A, Hudgins L, Uhrich S, Doyle DL, Silvey K, Scott RC, Cheng E, McGillivary B, Steiner RD, Olson D. Genetic counseling and screening of consanguineous couples and their offspring: Recommendations of the National Society of Genetic Counselors. 2002 JOGC 11(2):97-119.

28. Photograph credit: http://www.snof.org/maladies/toxemie_gravidique.html


References

29. Http://www.genetests.org – see Reviews section

30. Canadian College of Medical Geneticists – CF Testing / Screening Statement: http://ccmg.medical.org/pdf/ccmg_cf.pdf

31. Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, Desnick RJ (Subcommittee on Cystic Fibrosis Screening, Accreditation of Genetics Services Committee, ACMG). Laboratory standards and guidelines for population-base cystic fibrosis carrier screening. Genet Med 2001; 3;149-154.


Documents

The Genetics Education Project Comparison of Prenatal Screening Tests for the Detection of Down Syndrome Prepared by:June C Carroll MD CCFP FCFP Sydney