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Recommendations for Testing for Fetal Abnormalities Lee P. Shulman MD Northwestern Memorial Hospital Distinguished Physician and Professor and Chief Division.

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Presentation on theme: "Recommendations for Testing for Fetal Abnormalities Lee P. Shulman MD Northwestern Memorial Hospital Distinguished Physician and Professor and Chief Division."— Presentation transcript:

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

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

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10 Amniocentesis

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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

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18 Second Trimester Screening – Fetal Chromosome Abnormalities AFP – 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

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 Wald et al, J Med Screen 2003

23 Screening for Trisomy 21 Procedures needed Sensitivityto detect one case 30% (Age)100 30% (Age)100 60% (BC) 55 60% (BC) 55 80% (NT) 40 80% (NT) 40 90% (NT+BC) 35 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)

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30 Ethnicity and Genetic Disease Ethnic/Racial GroupDisorderScreening Test AcadianTay-SachsDNA molecular analysis serum hexosaminidase-A African-Americanssickle cell diseasepresence of sickle cell hemoglobin (sickledex); confirmatory hemoglobin electrophoresis Ashkenazi Jews Tay-SachsDNA molecular analysis serum hexosaminidase-A Canavan DNA molecular analysis Familial dysautonomiaDNA molecular analysis Mediterranean people-thalassemiamean corpuscular volume (MCV) less than 80% from CBC; confirmatory hemoglobin electrophoresis Southeast Asian and-thalassemiamean corpuscular volume Chinese ethnic(MCV) less than 80% from CBC; groupsDNA analysis All ethnic groupscystic fibrosisDNA molecular analysis - should be offered to Caucasians and Ashkenazi Jews, made available to all other groups

31 Epidemiology of Cystic Fibrosis Caucasians1/2,500 African-Americans1/18,000 Asian-Americans1/90,000 United States Affected30,000 Carriers8,000,000

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

33 Population Carrier Screening by Ethnic Group Ethnic Background Published Carrier Risk Range of Test Detection* Caucasian1/25 - 1/ % Ashkenazi Jewish 1/25 - 1/ % Hispanic1/ % African American 1/ % Asian American *varies by laboratory 1/ %

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

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

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

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


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