Genetic Screening and Pregnancy: Selecting the Best

Test for Your Patient

Britton Rink, MD, MS

The Ohio State University

Division of Maternal Fetal Medicine

ACOG Practice Bulletin January 2007

Screening and invasive testing options should be available to

all women REGARDLESS of maternal age

Low risk pregnant woman

High risk pregnant woman

Genetic Counseling

Traditional screening • 1st trimester

nuchal and AFP

• Second trimester quad screen

Declines screening/testin

g

NIPT (> 10 wks) Diagnostic testing • CVS (10+ wks)

• Amnio (> 15 wks)

Positive Borderline Negative

Positive

Direct Patient Inquiry

Confirm with diagnostic testing Recommend

diagnostic testing No further

testing

Genetic counseling to discuss results

If negative, consider CMP vs.

false positive

Ultrasound abnormality

The Ohio State University Algorithm for Aneuploidy Detection

SCREENING vs. INVASIVE testing

Maternal Screening

Maternal serum markers and ultrasound markers to detect increased risk of fetal trisomy 21, trisomy 18 and/or neural tube defects

– 1st trimester maternal serum screening (with or without nuchal translucency measurement)

– 2nd trimester maternal serum screening

– Other variations combining 1st and 2nd trimester screening results

– Ultrasound

– Circulating cell free fetal DNA

Screening

• Patient education points:

– ‘This is only a screening test’

– ‘The test is optional’

– ‘A negative result does not guarantee a healthy baby’

– ‘A positive result does not mean that the baby has a problem, BUT further testing (ultrasound & CVS or amniocentesis) would be offered’

– Offered to all patients regardless of age – ‘there is a small risk in every pregnancy for these conditions’

Detection of Aneuploidy

First trimester

screening

• Trisomy 21

• Trisomy 18

• Trisomy 13

• ? Congenital heart disease

• Other genetic conditions with increased NT

• DOES NOT SCREEN FOR NTD

• Trisomy 21

• Trisomy 18

• NTD

Second trimester

screening

FIRST TRIMESTER

First trimester: Serum and Ultrasound

• Nuchal Translucency

• Nasal Bone

• Free beta hCG and pregnancy-associated plasma protein A (PAPP-A)

– Free beta hCG

– PAPP-A

Nuchal Translucency

• Gestation 11-14 wks

• Crown-rump length 45-84 mm

• Mid-sagittal view

• Image size: head and thorax

• Neutral position

• Away from amnion

• Maximum lucency

• Callipers on-to-on

Criteria for proper measurement of nuchal translucency

Nicolaides KH. Fetal nuchal translucency. Am J Obstet Gynecol

2004

Clinical Scenario

• Mrs. Smith 32 y.o. G2P1001 at 11 weeks with prior child who had hypoplastic left heart syndrome.

– What do you tell her about screening for CHD using nuchal translucency?

Nuchal Translucency and CHD

Nuchal Translucency and CHD

• Fetuses with increased NT have an increased risk for congenital heart disease – no particular bias for one form of CHD over another

• NT measurement is only a modestly effective screening tool for all CHD when used alone – Simpson et al. (FASTER Consortium 2007) prospective study of

34 622 fetuses, found a sensitivity of only 15.4% using 2.0 multiples of the median (MoM) nuchal measurement

– it may indeed be effective in identifying specific CHD “likely to benefit” from prenatal diagnosis

• Combination of an increased NT, tricuspid regurgitation and an abnormal ductus venosus (DV) Doppler flow profile, is a strong marker for CHD

Clinical Scenario

• Mrs. Jones 38 y.o. G1P0 now at 20 weeks who was seen by MFM for increased nuchal translucency 4.0mm. She underwent CVS with normal karyotype and just had normal fetal echo.

– What should you tell her about potential outcomes for this pregnancy with all normal results?

Counseling • What is the change of a normal pregnancy

outcome with normal karyotype?

Nasal Bone Midface hypoplasia

Nasal Bone

•

Nasal skin

No bone present

Nasal Bone

• Absent in 1% fetuses normal karyotype

• Absent in 1st and 2nd trimester 60-65% fetuses with Down syndrome

• Absence in ethnic variation:

– African 5.8%

– Asian 3.4%

– Caucasian 2.6%

Clinical Scenario

• Mrs. Sanchez 37 y.o. G3P2002 at 11 weeks presents requesting most sensitive SCREENING test. She is not interested in invasive testing.

– What should you offer her?

Circulating cell free fetal DNA

Circulating cell free fetal DNA

Circulating cell free fetal DNA

Circulating cell free fetal DNA

• 4 labs offer the test clinically

• Evaluates chromosomes X,Y,13, 18 and 21

– Fetal RhD genotyping

• Different modalities of DNA analysis by each company

• Cost

• Genetic Counseling – pretest and posttest counseling

Circulating cell free fetal DNA (ccfDNA) Non invasive prenatal testing (NIPT)

• THIS IS A SCREENING TEST

– A patient with a positive test result should be referred for genetic counseling and should be offered invasive prenatal diagnosis for confirmation of test results

– A negative cell free fetal DNA result does not ensure an unaffected pregnancy

• Cell free fetal DNA testing should not be offered to low-risk women or women with multiple gestations because it has not been sufficiently evaluated in these groups…YET

Second Trimester

Quad Screen

• Analytes used (with maternal age):

– Alpha-fetoprotein (AFP)

– Unconjugated estriol (uE3)

– Beta-Human Chorionic Gonadotropin (b-HCG)

– Inhibin A

• Inhibin A not used in calculation of risk for trisomy 18

SCREENING ULTRASOUND

Screening Ultrasound

• Nuchal translucency (NT) and nasal bone (NB)

– Each with ~ 70% sensitivity detection DS

• Fetal anatomy – 18-20 weeks

– Offered for significant family history of detectable

structural defects or genetic syndrome(s), for f/u of

positive serum screens, for prenatal history of known

teratogens, etc.

– “Genetic Sonogram” sensitivity 75% detection DS *

Benacerraf, 2005

Second Trimester Ultrasound

Clinical Scenario

• 34 year-old G1P0 presents for second trimester ultrasound evaluation. Which of these findings is associated with the highest likelihood ratio for trisomy 21?

– Nuchal skin fold > 6mm

– Short humerus

– Echogenic bowel

– Echogenic intracardiac focus

Screening for Down Syndrome

Clinical Scenario

• 28-year old non-Hispanic white G1P0 undergoes mutation analysis for the recommended 23 mutations in the cystic fibrosis gene. She is not a carrier.

• TRUE/FALSE: Based on this test result, the patient has no risk of having a child with cystic fibrosis.

FALSE

Ethnicity-Based Genetic

Carrier Screening

• Purpose: To detect couples at risk for prenatally diagnosable genetic diseases

• Tests offered based on ethnic background

• Should be offered to patients:

– Seeking preconception counseling, OR

– Seeking infertility care, OR

– During the first or early second trimester of pregnancy

African-American Sickle Cell Cystic Fibrosis Beta-Thalassemia

1 in 10 1 in 65 1 in 75

Ashkenazi Jewish Gaucher disease Cystic Fibrosis Tay-Sachs disease Dysautonomia Canavan disease

1 in 15 1 in 26 – 1 in 29 1 in 30 1 in 32 1 in 40

Asian Alpha-Thalassemia Beta-Thalassemia

1 in 20 1 in 50

European American Cystic Fibrosis 1 in 25 - 1 in 29

French Canadian,

Cajun

Tay Sachs disease 1 in 30

Hispanic Cystic Fibrosis Beta-Thalassemia

1 in 46 1 in 30 - 1 in 50

Mediterranean Beta-Thalassemia Cystic Fibrosis Sickle Cell

1 in 25 1 in 29 1 in 40

Population Condition Carrier Frequency

Carrier Frequencies based on Ethnic Origin

Ethnicity-Based Genetic

Carrier Screening

• Ashkenazi Jewish Carrier Testing recommended by ACMG and ACOG

• Bloom syndrome • Canavan disease • Cystic fibrosis • Familial dysautonomia • Fanconi anemia group C • Gaucher disease • Mucolipidosis type IV • Niemann-Pick disease type A • Spinal Muscular Atrophy (SMA) • Tay-Sachs disease

Genetic Screening

• Spinal Muscular Atrophy – ACOG: preconception and prenatal screening for SMA is

not recommended in the general population at this time.

– ACMG: Because SMA is present in all populations, carrier testing should be offered to all couples regardless of race or ethnicity.

• Fragile X – ACOG/ACMG: Women with a family history of fragile X-

related disorders, unexplained mental retardation or developmental delay, autism, or premature ovarian insufficiency are candidates for genetic counseling and fragile X premutation carrier screening.

Although personalized genomic tests that provide information regarding the risk of development of multiple diseases may be important tools in the near future, their use is not recommended outside of a clinical trial until these tests are validated as clinically useful in appropriately designed prospective studies.

FUTURE

THANK YOU!

Background:

Fetal Nucleic Acids in Maternal Plasma

• First report of free fetal DNA in maternal

circulation. (Lo YMD et al. Lancet

1997;350:485-7)

• Fetal DNA clears rapidly from maternal

circulation after the baby is delivered. (Lo

YMD et al. Am J Hum Genet 1999;64:218-24)

• First report of free fetal RNA in maternal

circulation. (Poon LLM et al. Clin Chem

2000;46:1832-4)

• Prenatal diagnosis of fetal RHD status by

molecular analysis of maternal plasma. (Lo

YMD et al. N Engl J Med 1998;339:1734-8)

Options for Prenatal Diagnosis

Amniocentesis

Samples amniotic fluid

15 weeks earliest

1/200 -1/300 risk of miscarriage

CVS

Usually done between 10-13 weeks gestation

Samples placental tissue

1/100 risk for miscarriage

? Limb reduction defects