1. Recommendations for Testing for Fetal Abnormalities
Lee P. Shulman MD
Northwestern Memorial Hospital Distinguished Physician and Professor and Chief
Division of Reproductive Genetics
Department of Obstetrics and Gynecology
Feinberg School of Medicine, Northwestern University
We are very happy to be here to roll-out of MSS program. A big focus of this year’s meeting has been first trimester and integrated screening. We have partnered with Jefferson Hospital for many years. Jefferson Hospital has always been on the cutting edge in maternal fetal medicine just like Genzyme has.

2. Objectives
Describe the major ethical issues surrounding genetic testing for fetal abnormalities.
Discuss how health care providers can improve the genetics literacy of their patients to enhance their understanding of the benefits, risks, and limitations of genetic screening and testing for fetal abnormalities.
Identify when and how to refer patients seeking genetic testing for fetal abnormalities.

3. Screening is the testing of apparently well persons to identify those who might be at increased risk of having a disease.

4. Diagnosis is the testing of an individual to determine whether or not he a a particular disease or condition.

5. Increased Risk for Detectable Fetal Abnormalities
Advanced maternal age (> 35 years-old at estimated date of delivery
Family history of detectable Mendelian disorder
Parental chromosome rearrangement or aneuploidy
Exposure to specific chemical or radiation agents
Certain ultrasound findings
Positive maternal or genetic screening outcomes

6. Role of Genetic Counseling: Prior to Testing
Detailed review of family & medical history
Comprehensive pedigree analysis
Genetic risk assessment & interpretation
Genetic testing options, including risks, benefits & limitations
Provide educational materials
Facilitate patient informed consent

7. Chorionic Villus Sampling

10. Amniocentesis

12. Efficacy and Safety: CVS and Amniocentesis
Similar efficacy
Confined placental mosaicism with CVS
Cytogenetic success over 99%
Similar safety
More losses after CVS because it is performed at an earlier gestational age
Increased risk of loss with both procedures is approximately 0.5% over baseline

13. Screening Practices Second trimester 15.0 – 20.9 weeks
AFP (NTD), hCG, uE3, inhibin A
NTD, Down syndrome, trisomy 18
First trimester
10.3 – 13.8 weeks
hCG, PAPP-A, Nuchal translucency
Down syndrome, trisomy 18
Integrated Screening
Combines first and second trimester in a sequential, unified fashion
Cannot separate the two components
Most effective approach to Down syndrome, trisomy 18 detection
Allows for NTD detection

14. Applications - AFP
Neural Tube Defects
Down Syndrome
Trisomy 18

18. Second Trimester Screening – Fetal Chromosome Abnormalities
AFP
b – hCG
uE3
60% detection rate for Down syndrome, trisomy 18
Inhibin A
Detection rate may increase to 80%

19. The highlights of first trimester screening
Provides an early answer
Requires access to sonographers trained in NT measurement
Requires access to CVS
Does not provide a risk assessment for ONTD
As I mentioned earlier, we believe in offering you a menu of high-quality options because we know that there is not one test to address all patients.
Since each option has different components, each has different advantages and disadvantages.
For example 1st screen is the only option that reports in the first trimester--

20. Nuchal Translucency (NT)

21. Nuchal translucency (NT) A critical component
What is it?
Measurement of the fluid that collects behind the fetus’ neck
Measured by ultrasound between 10 and 14 weeks’ gestation
Size of fetus is 45 to 84 mm
Why is it important?
Indication of fetal distress/abnormalities
Trisomy 21, Trisomy 18, heart defects
More fluid indicates a greater the risk of an abnormality
10% of fetuses with NT of 3mm have major abnormalities
90% of fetuses with NT of 6mm have major abnormalities
Nicolaides et al The week scan 1999

22. Best first trimester markers: NT and PAPP-A
I know that one of your concerns is knowing the effect of using total hCG instead of free-B hCG. The strenght of any first trimester screening test come from the NT measurement. This is the best marker for DS. Based on SURUSS data,
Wald et al, J Med Screen 2003

23. Sensitivity to detect one case
Screening for Trisomy 21
Procedures needed
Sensitivity to detect one case
30% (Age) 100
60% (BC)
80% (NT)
90% (NT+BC) 35

24. Ultrasound as a Screening Tool
Improved ability to detect an increasing number of fetal anomalies
Able to reliably detect fetal anomalies in the first trimester
3-D/4-D
Increased ability to provide meaningful information to women and couples

25. Limitations of Ultrasound as a Screening Tool
Highly Subjective
Operator experience
Machine
Training
Quality Assurance
Difficult to Assess Ability to Provide Accurate Diagnosis
False Positive
False Negative

26. Anomalies Detectable by Ultrasound
Craniospinal: (anencephaly; spina bifida; encephalocele; hydrocephalus)
G.I.T: (omphalocele; gastroschisis; diaph hernia; duod atresia; colonic obstruction)
Urinary tract anomalies: (obstructive uropathy; polycystic kidney; renal agenesis; renal cysts)
Limb Deformities (limb reduction; skeletal dysplasia; limb-body wall defect).
Cardiac anomalies (ASD; VSD; hypoplastic anomalies; aortic arch; mitral atresia; cardiomyopthy)
Fetal tumors: (cystic hygroma; teratoma; neuroblastoma)

30. Ethnicity and Genetic Disease
Ethnic/Racial Group Disorder Screening Test
Acadian Tay-Sachs DNA molecular analysis
serum hexosaminidase-A
African-Americans sickle cell disease presence of sickle cell
hemoglobin (sickledex);
confirmatory hemoglobin
electrophoresis
Ashkenazi Jews Tay-Sachs DNA molecular analysis
Canavan DNA molecular analysis
Familial dysautonomia DNA molecular analysis
Mediterranean people b-thalassemia mean corpuscular volume
(MCV) less than 80% from CBC;
Southeast Asian and a-thalassemia mean corpuscular volume
Chinese ethnic (MCV) less than 80% from CBC;
groups DNA analysis
All ethnic groups cystic fibrosis DNA molecular analysis
- should be offered to Caucasians and Ashkenazi Jews, made available to all other groups

31. Epidemiology of Cystic Fibrosis
Caucasians 1/2,500
African-Americans 1/18,000
Asian-Americans 1/90,000
United States
Affected 30,000
Carriers 8,000,000

32. CYSTIC FIBROSIS GENE Located on 7q 250,000 bp (250kb) 27 exons
cDNA 6,100 bp
Cystic fibrosis transmembrane regulator; 1,480 amino acids

33. Population Carrier Screening by Ethnic Group
Background
Published
Carrier Risk
Range of
Test Detection*
Caucasian
1/25 - 1/29
78-90%
Ashkenazi
Jewish
95-97%
Hispanic
1/46
58-85%
African
American
1/65
60-80%
Asian
*varies by laboratory
1/90
33-38%

34. OFFERED
Physician or other health care worker initiates the counseling about CF screening
May be supplemented by written materials, videotape, CD, or other modalities
Similar to second trimester Maternal Serum Screening

35. RECOMMENDATIONS FOR MAKING CF SCREENING AVAILABLE
Low Risk Groups
African-Americans
Hispanics
Asian-Americans
No known admixture with
higher risk groups

36. MAKE AVAILABLE
Written material should be provided to lower risk racial or ethnic group(s)
Risk for having a child with CF
Sensitivity of CF screening
When requested, additional information or counseling should be provided
If desired, CF screening should be provided

37. CONCLUSIONS 3 generation family history Counseling when appropriate
Disorders, ethnicity, race
Counseling when appropriate
Current Standards
Sickle cell disease, - and -thalassemia, Jewish genetic disorders including Tay Sachs, Canavan, familial dysautonomia and CF