Sequential Screen
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Transcript Sequential Screen
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Genetic Testing in Pregnancy
Johanna Warren, MD
OAFP Women’s Health Winter Conference
January 19, 2014
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What genetic screening test do
you routinely offer your patients?
A.
B.
C.
D.
E.
F.
Quad/Penta screen
Integrated Screening
Nuchal Translucency (NT) only
Stepwise Sequential Screen
NIPT (cffDNA)
none
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Learning Objectives
Use
the concepts of pre-test probability,
positive and negative predictive values as they
apply to testing for fetal aneuploidy.
Outline
advantages and disadvantages of
various approaches to first-trimester and
second-trimester screening as well as invasive
diagnostic testing for Down syndrome.
Discuss
emerging cell-free fetal DNA (cffDNA)
technology and review indications for use in
screening.
Summarize
the current recommendations for
cystic fibrosis screening.
+ Statistics
Pre-test
probability
Prevalence of the disease
Post-test probability after one or more preceding tests
Rough clinical estimation
Positive
predictive value (PPV)
the likelihood that an individual with a positive test result
truly is affected/has the genetic condition
inherently dependent upon the prevalence
Negative
predictive value (NPV)
the likelihood that an individual with a negative test result
is truly unaffected/does NOT have the genetic condition
measure of test accuracy
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What Makes a Good Screening Test?
The condition should be an important health problem.
There should be an acceptable test for the condition.
High sensitivity to detect not yet clinically detectable condition
High specificity to minimize false positives
The test should be available to the population.
The test should be affordable.
There should be acceptable treatment for the condition.
There
should be a “latent stage” of the disease, allowing for
detection/testing before a critical point, during which
treatment would be optimal.
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What is the purpose of antenatal
genetic testing?
Assess
risk for chromosome abnormalities
particularly
Determine
Down syndrome & Trisomy 18
which pregnancies should be
offered invasive prenatal diagnosis
+ Who Should Be Screened?
ACOG
Practice Bulletin (2007)
All
pregnant women, regardless of their age,
should be offered screening and diagnostic
testing for aneuploidy.
Women should be counseled regarding the
differences between screening and invasive
diagnostic testing.
Ideally, patients
seen early in pregnancy
should be offered screening that combines
1st and 2nd trimester testing
Screening
test chosen will depend on availability
of NT US as well as CVS
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Testing for Fetal Aneuploidy –
Focus on Down Syndrome
(trisomy 21)
Explosion of available screening tests
Detection of Down Syndrome 90+% with non-invasive screening
tests
Confirmation diagnosis still requires invasive testing
Amniocentesis
Chorionic villus sampling
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Quick Review
Several
methods for combining first- and
second-trimester screening reach higher
detection rates for Trisomy 21 than either
first- or second-trimester screening alone.
Common
options:
Ultrasound:
Nuchal Translucency
Integrated Screenings
Quadruple/Penta Marker Screenings
Stepwise Sequential Screening
+ First Trimester - Ultrasound
Nuchal Translucency
(NT)
Normal: 1-3mm
Increased NT is an indication of a chromosomal
abnormality, single gene defect, or birth defects
(commonly cardiac defects)
Nasal
Bone
Absent/hypoplastic in 70% T21
Ductus Venosus
Detection rate 75%, FPR 5%
Tricuspid
– reversed a-wave flow
Regurgitation
Detection rate 67.3% in T21, FPR 5.2%
+ Integrated Screenings
Integrated
Screening
Ultrasound
for Nuchal Translucency (NT) + serum
PAPP-A/hCG analysis between 10-13.6wks GA;
results of these tests are HELD
Serum quad screen test between 15 -19 wks GA
At that time, the results of all the studies, combined
with risk assessment due to the patient's age, are
used to present a single-risk figure
Serum
Integrated Screening
first-trimester
serum PAPP-A/hCG test result is
combined with a second-trimester quad screen test
to provide a single-risk figure (no NT US)
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Quadruple Marker Screening
Measure
raw values of:
AFP
(alpha fetoprotein)
ue3 (unconjugated estriol)
hCG (human chorionic gonadotropin)
DIA (dimeric inhibin A)
Compare
to median value for the appropriate
gestational age (MoM)
Valid
between 14-22.9 weeks GA (optimal 1618wks); risk of NTD not provided for samples
collected prior to 15 weeks.
+ Stepwise Sequential Screening
First Trimester
NT US + serum PAPP-A analysis between 10-13.6wks
GA
Results combined with the patient's age-associated
risk,
Patient is given a risk assessment for aneuploidy
may choose at this time to undergo invasive testing
(e.g., amnio or CVS), or add quad screen test at 15-19
wks GA
Second Trimester
Quad screen test at 15-19 wks GA
a new risk is assessed based on the results of patient’s
age and both the first- and second-trimester screening
test results
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Sequential Screening
How
do you decide when to proceed with
invasive testing?
Risk
chorionic villus sampling (CVS) ~ 0.5-1/100
amniocentesis ~1/1000
After
of miscarriage (approximate; operator-specific)
1st trimester results return:
If risk is greater than ~1 in 50, offer CVS
If risk is less than ~1 in 1,000, advise no further testing is
necessary.
If risk is between these two (arbitrary) cutoffs, offer quad
screen test after 15 wks GA, and determine a new risk
assessment
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FASTER Trial Data
Screening Test
Best Detection
Rate for Down
Syndrome
NT alone
70%
Quad screen alone (2nd trimester)
81%
First Screen (with NT)
87%
Serum Integrated (1st tri PAPP-A/hcg + 2nd tri
quad)
88%
Sequential Screen (1st tri PAPP-A + NT + 2nd tri
quad)
94%
Integrated Screen (1st tri PAPP-A/hcg + NT + 2nd tri 96%
quad); patient does not receive results until 2nd
trimester testing complete
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What do you do with…
Normal
Other
Ultrasounds
Abnormal Serum Studies
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Normal Ultrasounds
Normal
ultrasound: 50-60% decrease in
risk for chromosome abnormalities
Remember
that at least 30% of fetuses with
Down syndrome have NO abnormal
ultrasound findings!
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Low 1st Trimester PAPP-A
Pregnancies with PAPP-A of ≤ 5%tile (0.4MoM) are at
increased risk for:
Spontaneous fetal loss < 24 wks GA
Low birth weight
Preeclampsia
Gestational HTN
Preterm birth and stillbirth
Preterm premature rupture of membranes
Placental abruption
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Abnormal 2nd Trimester Serum
Values
Elevated hcg
Elevated inhibin-A
Low uE3
preeclampsia
preeclampsia
steroid sulfatase deficiency
preterm delivery
IUGR
Smith-Lemi-Opitz syndrome
low birth weight infant
preterm delivery
congenital adrenal
hyperplasia
IUFD
adrenocorticotropin
deficiency
placental abruption
hypothalamic corticotropin
deficiency
anencephaly
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What’s next?
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Cell-free Fetal DNA (cffDNA)
Screening or Diagnosis?
Known as “Noninvasive Prenatal Testing” or “NIPT”
Technology uses circulating cell free fetal DNA found in the
maternal plasma
Thought to be derived primarily from placenta
New recognition of limitations of screening with pregnancies with
placental mosacisms
Unclear data for egg donor pregnancies
Available as early as 10th week of pregnancy
Cleared from maternal blood almost immediately after childbirth
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Cell-free Fetal DNA (cffDNA)
2012 publications (Sparks et al., Ashoor et al., Bianchi et al.)
targeted (chromosome-selective) sequencing of chromosomes 18
and 21
highly accurate
potentially more cost-effective
Technology can be expected to identify 98% of cases of T21
with a false-positive rate of < 0.5%.
Multiple different labs
MaterniT21plus by Sequenom
Verifi by Verinata
Harmony by Ariosa
+ Cell-free Fetal DNA (cffDNA) Labs
MaterniT21plus by Sequenom
>99% detection for T21, T18
~90% detection for T13
<1% false positive rate
Cost: $235-2700
Verifi by Verinata
>99% detection for T21, T18
~80% detection for T13
>90% detection for 45,X
<1% false positive rate
Cost: $200-1200
Harmony by Ariosa
>99% detection for T21, T18
~80% detection for T13
<1% false positive rate
Cost: up to $795
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Cell-free Fetal DNA (cffDNA)
ACOG Committee Opinion, Dec. 2012 – “Noninvasive
Prenatal Testing for Fetal Aneuploidy”
cffDNA testing should be an informed patient choice after
counseling and should not be part of routine prenatal laboratory
assessment.
cffDNA testing should not be offered to low-risk women or women
with multiple gestations (has not been studied).
A negative cffDNA test result does not ensure an unaffected
pregnancy.
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.
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Indications for Considering Use of
cffDNA for Screening
Maternal Age ≥ 35 years at delivery
Fetal ultrasound findings indicating increased risk of aneuploidy
CPCs?
IEF?
Clinodactyly?
Absent/hypoplastic nasal bone?
History of a prior pregnancy with a trisomy
Positive test result for aneuploidy (any serum test)
Parental balanced translocation with increased risk of fetal
trisomy 13 or 21.
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+ Considerations
Primary
insurers are generally reimbursing
for first-trimester screenings, including NT
ultrasounds as well as NIPT.
Are
there referral sites available to your
patients for appropriate genetic counseling
and NT US measurements? What about for
CVS and/or amniocentesis?
What
testing strategy makes the most sense
for your patients?
How
do you see it evolving in the next 1-2
years?
+ Testing for Cystic Fibrosis (CF)
Site
of genetic defect = CF Transmembrane
Regulator (CFTR) gene, a chloride channel protein
~ 1700 mutations of CFTR gene have been described
Disease
incidence: 1 in 2500 in the non-Hispanic
white population
Carrier
frequencies:
1/24-25 Caucasians of European descent or
Ashkenazi Jews
1/58 Hispanic American
1/61 African American
1/94 Asian American
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CF Genetic Testing
Difficult
to assign a single ethnicity to
individuals
ACOG
2011 Recommendation – offer CF
carrier screening to all women of
reproductive age
Need
to be screened only once
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CF Parental Genetic Testing
Sequential testing
Test mother for carrier state
If positive, test father
Concurrent testing
Test mother and father simultaneously
Advantage: can be done prior to conception
Limitation: depends on accurate ID of father
If both parents are unaffected but family hx of CF exists:
Genetic counseling
Identify if CFTR mutation analysis in affected family member is available
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Positive CF Testing
If both parents are carriers…
and prior to conception
offer ART options for diagnosis of embryo
and currently pregnant
offer CVS or amnio to confirm status of fetus
No in-utero treatments exist
Variable clinical scenarios, with median survival for patients
37yrs
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“Residual Risk”
Potential risk of having an affected child with CF after
testing is completed and is negative
Varies by race and current testing panel for gene
abnormalities
Will vary over time and by laboratory
Newborn screening panels that include CF screening
do not replace maternal carrier testing
+ Summary Recommendations
Genetic screening in pregnancy (and pre-conception!) is
rapidly getting more complex.
OHSU Online Course (FREE!)
0.5 CME credits available
www.ohsu.edu/prenatal-screening
Understand your patient population and your local
capabilities, specifically as they relate to genetic counseling,
ultrasound expertise, and diagnostic testing.
Develop practice workflows that allow women to access
early genetic screening should they desire.
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