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.

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 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--

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 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

Sensitivity to detect one case 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 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 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

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 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 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%

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 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