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

– 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 componentWhat 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 mmWhy 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

58% 63%76%

83%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

NT NT + age NT + age +PAPP-A

NT + age +PAPP-A +

HCG

Wald et al, J Med Screen 2003

Screening for Trisomy 21Screening for Trisomy 21

Procedures neededProcedures neededSensitivitySensitivity to detect one caseto detect one case

30% (Age)30% (Age) 100 100

60% (BC)60% (BC) 5555

80% (NT)80% (NT) 4040

90% (NT+BC)90% (NT+BC) 3535

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 TestAcadian Tay-Sachs DNA molecular analysis

serum hexosaminidase-A

African-Americans sickle cell disease presence of sickle cellhemoglobin (sickledex);confirmatory hemoglobin electrophoresis

Ashkenazi Jews Tay-Sachs DNA molecular analysisserum hexosaminidase-A

Canavan DNA molecular analysisFamilial dysautonomia DNA molecular analysis

Mediterranean people -thalassemia mean corpuscular volume(MCV) less than 80% from CBC; confirmatory hemoglobin electrophoresis

Southeast Asian and -thalassemia mean corpuscular volumeChinese 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 7qLocated on 7q

250,000 bp (250kb)250,000 bp (250kb)

27 exons27 exons

cDNA 6,100 bpcDNA 6,100 bp

Cystic fibrosis transmembrane Cystic fibrosis transmembrane regulator; 1,480 amino acidsregulator; 1,480 amino acids

Population Carrier Screening by Ethnic Group

EthnicBackground

PublishedCarrier Risk

Range ofTest Detection*

Caucasian 1/25 - 1/29 78-90%

AshkenaziJewish 1/25 - 1/29 95-97%

Hispanic 1/46 58-85%

AfricanAmerican 1/65 60-80%

AsianAmerican*varies by laboratory

1/90 33-38%

OFFERED

Physician or other health care Physician or other health care worker worker initiatesinitiates the counseling the counseling about CF screeningabout CF screening

May be supplemented by May be supplemented by written materials, videotape, written materials, videotape, CD, or other modalitiesCD, or other modalities

Similar to second trimester Similar to second trimester Maternal Serum ScreeningMaternal Serum Screening

RECOMMENDATIONS FOR MAKING CF SCREENING

AVAILABLE

Low Risk GroupsLow Risk Groups

African-AmericansAfrican-Americans HispanicsHispanics Asian-AmericansAsian-Americans

No known admixture withNo known admixture with higher risk groupshigher risk groups

MAKE AVAILABLE

Written material should be providedWritten material should be provided to lower risk racial or ethnic group(s)to lower risk racial or ethnic group(s)

Risk for having a child with CFRisk for having a child with CF Sensitivity of CF screeningSensitivity of CF screening

When requested, additional information When requested, additional information or counseling should be providedor counseling should be provided

If desired, CF screening should be If desired, CF screening should be providedprovided

CONCLUSIONS 3 generation family history3 generation family history

Disorders, ethnicity, raceDisorders, ethnicity, race

Counseling when appropriateCounseling when appropriate

Current StandardsCurrent Standards Sickle cell disease, Sickle cell disease, - and - and --

thalassemia, Jewish genetic thalassemia, Jewish genetic disorders including Tay Sachs, disorders including Tay Sachs, Canavan, familial dysautonomia and Canavan, familial dysautonomia and CFCF