Recommendations for Testing for Fetal Abnormalities

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. 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

6. 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

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 providea 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 11-14-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 Sensitivity to detect one case 30% (Age) 100 60% (BC) 55 80% (NT) 40 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 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

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. 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

34. 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

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

36. 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

37. 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