Transcript Genetic Testing in Pregnancy

Genetic Testing in Pregnancy
Lisbeth M. Lazaron, MD
March 2013
Genetic Screening Options
 Genetic Counseling
 Carrier screening for cystic fibrosis, SMA, MD,
hemoglobinopathy, Tay-Sachs, Fragile X
 1st Trimester Aneuploidy and nuchal translucency
screening (10 4/7-13 6/7 weeks)
 CVS (>9 weeks)
 MaterniT21 aneuploidy screening (>10 weeks)
 Amniocentesis (14-20 weeks)
 Quad screen (16-21 6/7 weeks)
 AFP alone (>14 weeks)
 Level 2 ultrasound screening for markers for
aneuploidies
Genetic Counseling
 Often the most cost effective option. Can refer
patients to Genetic counselors at UC or
Children’s Hospital
• EACH carrier test you obtain is $300-600; so a
$200 consult to help you narrow the options is a
good investment
• Can be done pre-conception
Carrier screening
 Can be done preconception on both males and
females, or at any time in pregnancy
o Hemoglobinopathy or Sickle screen
o Cystic Fibrosis carrier screen
o Tay-Sachs
o Fragile X
o SMA (Spinal Muscular Atrophy)
o MD (Muscular Dystrophy)
o Many more
Only needs to be tested ONCE in a life-time, not
each pregnancy!!
Cystic Fibrosis screening
 There are 1700 known mutations of the CFTR gene, screening
only the 25 most common mutations
•
The incidence of CF in 1/2500 and is autosomal recessive
•
98% of males with CF will have primary infertility due to agenesis
of the vas deferens
•
Females with CF have no infertility, but do have high risk
pregnancies
•
Carrier risk varies by race White
1/25
Hispanic
1/58
Black
1/61
Asian
1/94
Cost not covered by OB Special program-counsel before ordering!
1st Trimester Aneuploidy Screen
“Ultrascreen”
 Tests for Trisomy 13,18, 21 by a combination of fetal Nuchal
Translucency ultrasound and blood tests for free Beta-HCG and
PAPP-A (Pregnancy Associated Plasma Protein-A)
•
Timing specific to 10 4/7-13 6/7 weeks
•
Nuchal translucency needs to be done by perinatology with
experience, not available in all centers
•
Does NOT include testing for ONTD, will still need AFP later
•
Can do NT alone at 12-13 weeks with 76% PPV
•
Costs $600, covered by most insurances
Cost not covered by OB Special program-counsel before ordering!
MaterniT21-aneuploidy screening
•
Measures circulating free fetal DNA in maternal blood sample
•
Tests for Trisomy 13,18, 21 (Down)
•
Can be done at 10 weeks
•
Validated on high risk pregnancies only (AMA, abnormal Quad,
prior affected child, U/S finding with possible aneuploidy)
•
Not valid on twins
•
Currently FREE if getting perinatal consult or level 2 U/S at
Christ
•
Will still need AFP at 15-20 weeks for ONTD
•
98% specific; 0.5% false +
CVS-Chorionic Villi Sampling
 CVS 9-14 weeks (1 week for results).
•
Recommended for women with AMA or high risk for genetic
abnormalities, or after abnormal Ultrascreen or MaterniT21
testing
•
Chromosome testing so broad genetic array available
•
Maternal tissue sampling errors in inexperienced hands (1% risk
of mosaicism)
•
Trans-cervical or trans-vaginal approach
•
1/300 or 1/500 procedure related pregnancy losses in
EXPERIENCED hands
•
10X increase in limb reduction defects if done before 9 weeks, so
early test NO LONGER RECOMMENDED
•
Will still need AFP at 15-20 weeks for ONTD
Maternal Age-related Genetic Risks
AGE
Risk of Down
Risk of ALL Gene
30
1:940
1:384
35
1:353
1:178
40
1:85
1:62
45
1:35
1:18
Risk of pregnancy loss with CVS/amnio 1:400
Amniocentesis
 Amniocentesis 14-20 weeks (2 weeks for results)
•
Recommended for women with AMA or high risk genetic issues,
or after abnormal QUAD screen
•
Chromosome testing so broad genetic array available
•
takes longer for fetal cells to grow in culture, but fewer maternal
sampling errors (0.25% risk of mosaicism)
•
1/300 to 1/500 procedure related pregnancy losses
•
Early amniocentesis (11-13 weeks) 1/40 losses and more culture
failures—NO LONGER RECOMMENDED
•
Will still need AFP at 15-20 weeks for ONTD
Quad Screen
 Measures AFP, hCG, estriol and Inhibin-A
•
Screens for trisomy 21 (Down), trisomy 18 and ONTD (spina
bifida)
•
Accurate when done at 16-21 6/7 weeks, may need to have lab
re-calculate values if dating changes after test is done
•
Most commonly offered test but sensitivity is low (67% true +)
•
Costs $150 dollars
This test is covered on OB Special program
 Doing both an Ultrascreen & Quad screen and integrating the
statistical results significantly improves the specificity
AFP for ONTD
 MSAFP Maternal Serum Alpha Feto Protein
• Tests for ONTD only
• Done at 15-20 weeks
• Circulating levels vary based on weeks gestation and
number of fetuses so most common cause for abnormal is
dating errors or multiple gestation
• Follow an abnormal with a level 2 anatomy scan for
confirmation of ONTD
Level 2 U/S for aneuploidy markers
First trimester
 Nuchal translucency alone for triploidies 13,18,21
•
optimal timing is 12-13 weeks
•
76% true + 4% false +
 Absent Nasal bone
•
Only in experienced ultrasonographers (more common in UK)
•
timing 11-14 weeks
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Diagnostic for trisomy 13, 18, 21 & Turners
•
67-80% true+, 0.2-1.4% false +
•
Wide ethnic variances in euploid fetus with absent nasal bones,
from 2.8% in Caucasians to 10.4% in Afro-Carribean
Level 2 U/S for aneuploidy markers
Second Trimester
 Significant Markers
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Thickened nuchal fold (NOT the same as nuchal translucency)
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Cardiac defects
 “Soft” Markers
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Pyelectasis
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Shortened femur or humerus
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Echogenic bowel
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Intracardiac echogenic focus
21.9% false positive rate, but a normal test reduces
a priori risk by 88%
Sensitivities & Specificities
Test
False +
True +
 Quad screen
5%
69%
 NT, HCG, Papp-A
5%
82-86%
 NT alone
4%
76%
 Integrated
5%
95%
 CVS & Amnio
0%
99%
0.5%
98%
 MaterniT21
 U/S for aneuploidy
21.9%
67-80%
What to do?
 Options for testing depend on when the patient
presents for prenatal care, their risk factors and
their preferences and tolerance for risks & costs
of procedures
 Talk to the patient FIRST (or offer genetic
counseling)
 Order tests AFTER