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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.

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recommendations for testing for fetal abnormalities

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
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.
slide3
Screening is the testing of apparently well persons to identify those who might be at increased risk of having a disease.
slide4
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

Increased Risk for Detectable Fetal Abnormalities
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

Role of Genetic Counseling:Prior to Testing
efficacy and safety cvs and 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
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
Applications - AFP
  • Neural Tube Defects
  • Down Syndrome
  • Trisomy 18
second trimester screening fetal chromosome abnormalities
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
The highlights of first trimester screening
  • Provides an early answer
  • Requires access to sonographers trained in NT measurement
  • Requires access to CVS
  • Does not providea risk assessment for ONTD
nuchal translucency nt a critical component
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
Best first trimester markers: NT and PAPP-A

Wald et al, J Med Screen 2003

slide23

Screening for Trisomy 21

Procedures needed

Sensitivity to detect one case

30% (Age) 100

60% (BC) 55

80% (NT) 40

90% (NT+BC) 35

ultrasound as a screening tool
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
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
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
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

serum hexosaminidase-A

Canavan DNA molecular analysis

Familial dysautonomia DNA molecular analysis

Mediterranean people b-thalassemia mean corpuscular volume

(MCV) less than 80% from CBC;

confirmatory hemoglobin

electrophoresis

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

epidemiology of cystic fibrosis
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
cystic fibrosis gene
CYSTIC FIBROSIS GENE
  • Located on 7q
  • 250,000 bp (250kb)
  • 27 exons
  • cDNA 6,100 bp
  • Cystic fibrosis transmembrane regulator; 1,480 amino acids
population carrier screening by ethnic group

Ethnic

Published

Range of

Background

Carrier Risk

Test Detection*

Caucasian

1/25 - 1/29

78-90%

Ashkenazi

95-97%

1/25 - 1/29

Jewish

Hispanic

1/46

58-85%

African

1/65

60-80%

American

Asian

1/90

33-38%

American

*varies by laboratory

Population Carrier Screening by Ethnic Group
offered
OFFERED
  • Physician or other health care worker initiatesthe 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
RECOMMENDATIONS FOR MAKINGCF SCREENING AVAILABLE
  • Low Risk Groups
      • African-Americans
      • Hispanics
      • Asian-Americans
  • No known admixture with
  • higher risk groups
make available
MAKE AVAILABLE
  • Written material should be providedto 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
CONCLUSIONS
  • 3 generation family history
    • Disorders, ethnicity, race
  • Counseling when appropriate
  • Current Standards
    • Sickle cell disease, - and -thalassemia, Jewish genetic disorders including Tay Sachs, Canavan, familial dysautonomia and CF