Transcript Huntington family - UNC School of Medicine

Tools of Prenatal
Diagnosis
Julie Moldenhauer, MD
Reproductive Genetics
Maternal Fetal Medicine
Obstetrics and Gynecology
Objectives:
•
Discuss various prenatal screening and
testing tools
•
Discuss the timing of the various tools in
gestation
•
Discuss benefits and risks of various
options
•
Review the difference between screening
and testing
Baseline Risk for Birth Defects in
the General Population is
3-5%
What Can We Diagnose in
the Prenatal Setting?
•
Structural Abnormalities
•
Growth Abnormalities
•
Hematologic Abnormalities
•
Congenital heart disease
•
Spina bifida
•
Anemia
•
Gastroschisis
•
Thrombocytopenia
•
Chromosomal Abnormalities
•
Functional Defects
•
Trisomy 21
•
Arthrogryposis
•
Triploidy
•
Renal dysfunction
•
Infections
•
Syndromes
•
Parvovirus
•
Skeletal Dysplasia
•
Cytomegalovirus
•
Diabetic embryopathy
•
Toxoplasmosis
Prenatal Diagnosis Tools
•
History****
• Personal History
• Family History
•
Population Screening
•
Serum Screening
•
Ultrasound
Oaklandcc.edu
•
Fetal MRI
•
Invasive Diagnosis
• Chorionic villus sampling
• Amniocentesis
History is a Screening Tool!
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Maternal Age
•
• What medications?
• > 35 years at delivery
•
Obstetric History
• Prior baby born with Down
syndrome
• When was the exposure?
•
• Is she exposed to high
doses of radiation?
Medical History
• Is mom diabetic? How well
controlled is her sugar?
• Does she have PKU?
• Is she hypertensive?
Environmental
Exposures
• Does she work in a
preschool and was
exposed to parvovirus?
• Prior stillbirth
•
Medication Exposures
•
Family History
• Brother with hemophilia
• Uncle with cystic fibrosis
• Ethnic background
• Consanguinity
As maternal age increases, the risk for aneuploidy increases.
This is due to maternal meiotic nondisjunction.
Maternal age > 35 at the time of delivery is considered
“Advanced Maternal Age” or AMA
Down syndrome phenotype caused by trisomy 21
Down syndrome phenotype caused by 14;21 translocation
The risk for recurrence of chromosome abnormalities is
dependent upon the genetic mechanism involved.
Trisomy: 1% or maternal age-related risk
Translocation:
Maternal carrier: 10-15%
Paternal carrier: 2%
Maternal Diabetes: Reproductive Risks
• Obstetric
• Spontaneous preterm labor
• Polyhydramnios
• Preeclampsia (15-20%)
• Intrauterine growth
restriction
• Shoulder dystocia
• Cesarean delivery
Caudal
Regression
Syndrome
• Fetal and Neonatal
• Congenital anomalies: 6-12%
• Intrauterine fetal demise
• Macrosomia – Shoulder
dystocia
• Growth restriction
• Hyperbilirubinemia
• Hypoglycemia
• RDS
• Polycythemia
• Organomegaly
• Long term – obesity and
carbohydrate intolerance
ACOG Practice Bulletin #60: Pregestational Diabetes Mellitus, March 2005
Teratogen Exposure
<17 days
None, “ALL or NONE”
15-25
CNS
20-30
Axial skeleton, limb
buds, musculature
Eyes, heart, lower
limbs
Organogenesis
complete
Fetal growth
25-40
56
>60
Teratogen Exposure
•
•
•
•
•
•
•
•
•
Examples:
Accutane
ACE inhibitors
Lithium
Antiepileptic drugs (AEDs)
Anticoagulants: warfarin
Antidepressants
Methotrexate
Thalidomide
• Fetal effects are timing
and dose dependent
• Each medication is assigned a
pregnancy category based on
available data; A-D, X
• www.Reprotox.org
• www.otispregnancy.org
Ultrasound images of fetal hydrops – abnormal collection of fluid in multiple
body compartments.
Mom works at a daycare where there was a Parvovirus B19 or Fifth Disease
outbreak 4 weeks ago. Parvovirus causes fetal aplastic anemia that can be
life-threatening.
Suspicion of diagnosis by altered maternal serum titers of Parvo IgG and IgM
and confirmed by amniotic fluid PCR for Parvo.
Confirmed Parvo infection in a fetus with hydrops can be treated with
intrauterine blood transfusions.
= MR
= asthma
6
n
n
2
2
= TSC
Fetal Ultrasound Showing Cardiac
Rhabdomyoma
Fetal MRI Showing Tubers
Prenatal Findings Consistent with Tuberous
Sclerosis Confirmed as Neonate
Screening for Genetic Disease
Ethnic Group
Disease
African American
Sickle Cell Disease: 1/12
Mediterranean
Beta-Thalassemia: 1/30
Southeast Asian
Alpha-Thalassemia: 1/20
Caucasian
Cystic Fibrosis: 1/25
ASHKENAZI JEWISH ANCESTRY
GENETIC CARRIER TESTING
Disease Incidence
Carrier Frequency
Detection rate
Tay-Sachs disease
1/3000
1/30
98% by Hex A test,
94% by DNA
Canavan disease
1/6400
1/40
98%
Cystic Fibrosis
1/2500-3000
1/29
97%
Familial
Dysautonomia
1/3600
1/32
99%
Fanconi Anemia
Group C
1/32,000
1/89
99%
Niemann-Pick
disease type A
1/32,000
1/90
95%
Mucolipidosis IV
1/62,500
1/127
95%
Bloom syndrome
1/40,000
1/100
95-97%
1/900
1/15
95%
Gaucher’s disease
ACOG Committee Opinion Number 298, August 2004
Testing and screening options should be made
available to all pregnant women
Prenatal Screening & Testing
When
Screening Definitive
(risk estimate)
(Invasive)
First
Trimester
FIRST screen*
Ultrasound
CVS
Second
Trimester
Maternal Serum
Screen*
Amnio
Cordo
Ultrasound
*First and Second Trimester Integrated and
Sequential Screening
Test Performance

Detection rate – the percentage of
affected that are test “positive”
– (the higher, the better)

False positive rate – the percentage of
unaffected that are test “positive”
– (the lower, the better)
Goals in Prenatal Screening:

High sensitivity - low false positive rate

Wide availability

Reproducibility and accuracy
– Human error, testing conditions
First Trimester Screening
•
11-13 6/7 weeks
(CRL 39-79 mm)
•
Maternal serum sample for
PAPP-A and Free b-HCG
PAPP-A
T21
T18
•
Ultrasound for Nuchal
translucency
•
Detection Rates:
• 80% for Trisomy 21
• 90% for Trisomy 18
• Does not screen for NTDs
b-HCG
Increased NT vs Cystic Hygroma

Increased NT > 95th%
– With or without septations

Structural defects
– Heart defects most common

Syndromic associations
 Chromosomal defects
NT > 3 mm is
ABNORMAL
– Exponential increase with
increased NT
– 50% Down syndrome
– 25% Trisomy 13 or 18
– 10% Turner Syndrome
– 5% Triploidy
– 10% other
Second Trimester Serum Screening:
Chromosome Abnormalities
•
Maternal Serum Screening
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15-20 weeks
•
Triple screen: 60% for T21
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Quad screen: 70% for T21
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Gestational Age Dependent**
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Targeted Ultrasound
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50% aneuploid fetuses will have ultrasound markers
Serum Screening Test Performance
at a fixed 5% False Positive Rate
(Dating by Ultrasound)
Prediction
100
SURUSS
74%
DR at 5% FPR
80
66%
81%
76%
69%
60
42%
59%
40
37%
20
0
Wald et al. 2000
Malone et al. 2005
30%
AGE
+AFP
+hCG
+uE3
single
double
triple
2nd trimester
+InhA
quadruple
FASTER
Second Trimester Serum Screening:
Neural Tube Defects
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Neural Tube Defects
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Spina Bifida
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Anencephaly
•
AFP increased in “open” defects
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Sensitivity
•
•
90% anencephaly
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80-85% open spina bifida
False positive – 3-4%
Interpreting a Quadruple Screen
AFP
HCG/
Inhibin
uE3
T21
T18
NTD
SLO
Bottom Line: AFP is increased with NTDs and
decreased with chromosome abnormalities
Elevated MSAFP
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Incorrect Dates – most common reason
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Multiples
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Congenital Nephrosis
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Ventral Wall Defects
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IUFD
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Adverse Pregnancy Outcomes
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Stillbirth
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Placental abruption
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Preterm labor
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Oligohydramnios
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IUGR
Ultrasound detection of
aneuploidy
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Detection rates
Trisomy
21
Trisomy
18
Trisomy
13
Second trimester sonographic markers of Down syndrome
Nuchal Fold
CPC
Duodenal atresia
Pyelectasis
AV Canal
Clinodactyly
Trisomy 18
Edward Syndrome
• Close to 90% detected by prenatal scan
• US:
– Growth restriction
– Clenched fists
– >90% with cardiac defects
– Multiple malformations
• Grim prognosis
– 50% Stillbirth
– 50% die within the first week
– 5-10% survive the first year
Trisomy 13
Patau Syndrome
• > 90% detected prenatally
• US findings:
– Midline defects including clefts,
holoprosencephaly and NTDs
– >90% have cardiac defects
– Multiple structural abnormalities
• Grim prognosis
– High rate of miscarriage
– 80-85% die within first month
– 80-85% die within first year
Fetal Anatomy by Ultrasound
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Routinely offered with prenatal care
•
Performed in the second trimester
•
18-20 weeks optimal
•
Basic guidelines
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Level of performance dependent upon
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Who performs the scan
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Where the scan is performed
•
Level of equipment
Gastroschisis
Ventral Wall Defect
Located to the Right of the Umbilicus with NO Membrane Covering
Elevated MSAFP Levels
Not Associated with Chromosome Abnormalities
Increasing Incidence 1/10,000 >>>2-3/10,000
NTDs
•
Ultrasound detects 90-95%
•
Detection up to 98% with Ache by
amniocentesis
•
100% detection for anencephaly
•
Role of Folic Acid in Prevention:
•
All patients 0.4 mg per day
•
Previously affected 4mg per day
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One month prior to conception and throughout first
trimester
•
Decrease recurrence by up to 70%
Lemon Sign
Meningomyelocele Sac
Banana Sign
Meningomyelocele Sac on Newborn
PGD: Preimplantation Genetic Diagnosis
Pearls for Invasive Testing
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Risk for Sensitization
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Mom Rh negative – Rhogam
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Other antibodies may increase risk
•
Risk for Infection transmission
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Hepatitis B
•
Hepatitis C
•
HIV
•
Need to know familial mutations prior to
performing invasive testing
Chorionic Villus Sampling
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Performed 10-14 weeks
•
Does not test for ONTD
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Technique – “Placental biopsy”
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Transabdominal
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Transcervical
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Risk for limb reduction defects if
performed < 9 weeks
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Loss rate 1/100-1/200
•
Risk for mosaicism (~1%)
CVS
Transcervical
Transabdominal
Performed at 10-14 weeks
Amniocentesis
•
> 15 weeks
•
Loss rate 1/200 (probably closer to 1/3001/500)
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Tests for ONTD
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Technique
•
Fine gauge needle
•
Ultrasound guidance
•
Aspiration of 20-30 cc of fluid
AMNIOCENTESIS
PERFORMED ROUTINELY 15-20 WEEKS
Ultrasound Guided Procedure
Cordocentesis
•
Percutaneous Umbilical Blood Sampling
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Loss rate 1/100-1/200
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Typically done after 18 weeks
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Ability for:
•
Rapid karyotype
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Blood/platelet counts
•
Direct fetal injections/transfusions
Fetal Blood Sampling
“PUBS”
Conclusions
Many options for screening and testing.
 Prenatal screening should provide the
most effective test to the greatest
number of women.
 The best method of screening is yet to
be determined.
 Patient preference should be
considered.
 Testing and screening should be
available to all women.
