Transcript Selling Genzyme Genetics’ Maternal Serum Screening Program

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
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.
Screening is the testing
of apparently well persons
to identify those who
might be at increased risk
of having a disease.
Diagnosis is the testing
of an individual to
determine whether or not
he a a particular disease
or condition.
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

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

Chorionic Villus Sampling
Amniocentesis
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
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
Applications - AFP

Neural Tube Defects

Down Syndrome

Trisomy 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%
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
Nuchal Translucency (NT)
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 11-14-week scan 1999
Best first trimester markers:
NT and PAPP-A
Contribution to detection rate of first trimester markers
90%
80%
70%
60%
50%
40%
30%
76%
58%
63%
NT
NT + age
83%
20%
10%
0%
Wald et al, J Med Screen 2003
NT + age +
PAPP-A
NT + age +
PAPP-A +
HCG
Screening for Trisomy 21
Sensitivity
Procedures needed
to detect one case
30% (Age)
100
60% (BC)
55
80% (NT)
40
90% (NT+BC)
35
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
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

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)
Ethnicity and Genetic Disease
Ethnic/Racial Group Disorder
Acadian
Tay-Sachs
Screening Test
African-Americans
sickle cell disease
presence of sickle cell
hemoglobin (sickledex);
confirmatory hemoglobin
electrophoresis
Ashkenazi Jews
Tay-Sachs
DNA molecular analysis
serum hexosaminidase-A
DNA molecular analysis
DNA molecular analysis
Canavan
Familial dysautonomia
DNA molecular analysis
serum hexosaminidase-A
Mediterranean people
b-thalassemia
mean corpuscular volume
(MCV) less than 80% from CBC;
confirmatory hemoglobin
electrophoresis
Southeast Asian and
Chinese ethnic
groups
a-thalassemia
mean corpuscular volume
(MCV) less than 80% from CBC;
DNA analysis
All ethnic groups
cystic fibrosis
DNA molecular analysis
- should be offered to Caucasians and Ashkenazi Jews, made available to all other groups
Epidemiology of Cystic Fibrosis
Caucasians
 African-Americans
 Asian-Americans


1/2,500
1/18,000
1/90,000
United States


Affected
Carriers
30,000
8,000,000
CYSTIC FIBROSIS GENE
 Located
 250,000
 27
on 7q
bp (250kb)
exons
 cDNA
 Cystic
6,100 bp
fibrosis transmembrane
regulator; 1,480 amino acids
Population Carrier Screening by
Ethnic Group
Ethnic
Background
Published
Range of
Carrier Risk Test Detection*
Caucasian
1/25 - 1/29
78-90%
Ashkenazi
Jewish
1/25 - 1/29
95-97%
1/46
58-85%
Hispanic
African
1/65
American
Asian
1/90
American
*varies by laboratory
60-80%
33-38%
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
RECOMMENDATIONS FOR MAKING CF
SCREENING AVAILABLE
 Low
Risk Groups
 African-Americans
 Hispanics
 Asian-Americans
 No
known admixture with
 higher risk groups
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
CONCLUSIONS
3

generation family history
Disorders, ethnicity, race
 Counseling
 Current

when appropriate
Standards
Sickle cell disease, a- and bthalassemia, Jewish genetic
disorders including Tay Sachs,
Canavan, familial dysautonomia
and CF