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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


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

p Advanced maternal age (> 35 years-old at

estimated date of delivery

p Family history of detectable Mendelian

disorder

p Parental chromosome rearrangement or

aneuploidy

p Exposure to specific chemical or radiation

agents

p Certain ultrasound findings

p Positive maternal or genetic screening

outcomes


Current Approaches to Prenatal

Diagnosis

p Maternal Age

p Past Pregnancy History

p Ultrasound

p Serum Screening

p Family History of

Detectable Genetic

Disorders


Role of Genetic Counseling:

Prior to Testing

p Detailed review of family & medical

history

p Comprehensive pedigree analysis

p Genetic risk assessment &

interpretation

p Genetic testing options, including

risks, benefits & limitations

p Provide educational materials

p Facilitate patient informed consent


Chorionic Villus Sampling


Amniocentesis


Efficacy and Safety:

CVS and Amniocentesis

p Similar efficacy

• Confined placental mosaicism with CVS

• Cytogenetic success over 99%

p 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


New ACOG Guidelines:

Prenatal Screening and Diagnosis

p Age no longer the sole reason to offer

invasive testing

p All women, regardless of age or risk, are

to be offered invasive testing and prenatal

screening

p Screening should be multimarker and can

incorporate newer screening modalities

using first-trimester ultrasound


Screening Practices

p

p

p

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

p Neural Tube Defects

p Down Syndrome

p Trisomy 18


p AFP

Second Trimester Screening – Fetal

p b – hCG

p uE3

Chromosome Abnormalities

• 60% detection rate for Down syndrome,

trisomy 18

p Inhibin A

• Detection rate may increase to 80%


WEEK 5

WEEK 6 WEEK 7

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WEEK13

WEEK

WEEK 13

WEEK 14

WEEK 15 WEEK 16

WEEK 17

WEEK 18 WEEK 19

WEEK 20

WEEK 21

First trimester screening

Provides information about risk early in pregnancy

• Down syndrome detection rate: 83%

• False positive rate: 5%

• OAPR: 1 in 25

Approximately one out of every 25 women with a positive

first trimester screening result will have a fetus affected with

Down syndrome

• Markers: NT + PAPP-A + hCG

• Timing: 10w 3d - 13w 6d

• Requires: NT measurement

ONTD screening in second trimester

WEEK 5

WEEK 6

WEEK 7

WEEK 8

WEEK 9

WEEK 10

WEEK 11

WEEK 12

FIRST TRIMESTER

13

WEEK 14

WEEK 15

WEEK 16

WEEK 17

WEEK 18

WEEK 19

WEEK 20

SECOND TRIMESTER

WEEK 21

10-13 weeks


The highlights of first trimester

screening

p Provides an early answer

p Requires access to sonographers trained

in NT measurement

p Requires access to CVS

p Does not provide a risk assessment for

ONTD


Nuchal Translucency (NT)


Nuchal translucency (NT)

A critical component

What is it

p Measurement of the fluid that collects behind the fetus’

neck

p Measured by ultrasound between 10 and 14 weeks’

gestation

p Size of fetus is 45 to 84 mm

Why is it important

p

p

p

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


Screening for Trisomy 21

Sensitivity

Procedures needed

to detect one case

30% (Age) 100

60% (BC) 55

80% (NT) 40

90% (NT+BC) 35


Ultrasound as a Screening Tool

p Improved ability to detect an

increasing number of fetal anomalies

p Able to reliably detect fetal

anomalies in the first trimester

p 3-D/4-D

p Increased ability to provide

meaningful information to women

and couples


Limitations of Ultrasound as a

Screening Tool

p Highly Subjective

• Operator experience

• Machine

• Training

• Quality Assurance

p Difficult to Assess Ability to Provide

Accurate Diagnosis

• False Positive

• False Negative


Anomalies Detectable by Ultrasound

p Craniospinal: (anencephaly; spina bifida;

encephalocele; hydrocephalus)

p G.I.T: (omphalocele; gastroschisis; diaph

hernia; duod atresia; colonic obstruction)

p Urinary tract anomalies: (obstructive

uropathy; polycystic kidney; renal agenesis;

renal cysts)

p Limb Deformities (limb reduction; skeletal

dysplasia; limb-body wall defect).

p Cardiac anomalies (ASD; VSD; hypoplastic

anomalies; aortic arch; mitral atresia;

cardiomyopthy)

p 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

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


Clinical Presentation of

Cystic Fibrosis


Epidemiology of Cystic Fibrosis

p Caucasians 1/2,500

p African-Americans 1/18,000

p Asian-Americans 1/90,000

• United States

p Affected 30,000

p Carriers 8,000,000


Survival Curve for CF Patients

Percent Survival

100

90

80

70

60

50

40

30

20

10

0

30.6 years

5 10 15 20 25 30 35 40 45

Age in Years

Source: CF Foundation National CF Patient Registry, 1997


CYSTIC FIBROSIS GENE

pLocated on 7q

p250,000 bp (250kb)

p27 exons

pcDNA 6,100 bp

pCystic fibrosis transmembrane

regulator; 1,480 amino acids


Population Carrier Screening by

Ethnic Group

Ethnic

Background

Published

Carrier Risk

Range of

Test Detection*

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

Ashkenazi

Jewish

1/25 - 1/29 95-97%

Hispanic 1/46 58-85%

African

American

1/65 60-80%

Asian

American

1/90 33-38%

*varies by laboratory


OFFERED

p Physician or other health care

worker initiates the counseling

about CF screening

p May be supplemented by

written materials, videotape,

CD, or other modalities

p Similar to second trimester

Maternal Serum Screening


RECOMMENDATIONS FOR MAKING CF

SCREENING AVAILABLE

p Low Risk Groups

p African-Americans

Americans

p Hispanics

p Asian-Americans

Americans

p No known admixture with

p higher risk groups


MAKE AVAILABLE

p Written material should be provided

to lower risk racial or ethnic group(s)

p Risk for having a child with CF

p Sensitivity of CF screening

p When requested, additional information

or counseling should be provided

p If desired, CF screening should be

provided


CONCLUSIONS

p 3 generation family history

• Disorders, ethnicity, race

p Counseling when appropriate

p Current Standards

• Sickle cell disease, a- and b-

thalassemia, Jewish genetic

disorders including Tay Sachs,

Canavan, familial dysautonomia

and CF

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