Tools of Prenatal Diagnosis Julie Moldenhauer, MD Reproductive Genetics Maternal Fetal Medicine...
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Transcript of Tools of Prenatal Diagnosis Julie Moldenhauer, MD Reproductive Genetics Maternal Fetal Medicine...
Tools of Prenatal Tools of Prenatal DiagnosisDiagnosis
Julie Moldenhauer, MDJulie Moldenhauer, MDReproductive GeneticsReproductive Genetics
Maternal Fetal MedicineMaternal Fetal MedicineObstetrics and GynecologyObstetrics 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
• Congenital heart disease
• Spina bifida
• Gastroschisis
• Chromosomal Abnormalities
• Trisomy 21
• Triploidy
• Infections
• Parvovirus
• Cytomegalovirus
• Toxoplasmosis
• Growth Abnormalities
• Hematologic Abnormalities
• Anemia
• Thrombocytopenia
• Functional Defects
• Arthrogryposis
• Renal dysfunction
• Syndromes
• Skeletal Dysplasia
• Diabetic embryopathy
Prenatal Diagnosis ToolsPrenatal Diagnosis Tools
• History****
• Personal History
• Family History
• Population Screening
• Serum Screening
• Ultrasound
• Fetal MRI
• Invasive Diagnosis
• Chorionic villus sampling
• Amniocentesis
Oaklandcc.edu
History is a Screening Tool!History is a Screening Tool!
• Maternal Age
• > 35 years at delivery
• Obstetric History
• Prior baby born with Down syndrome
• Prior stillbirth
• Medical History
• Is mom diabetic? How well controlled is her sugar?
• Does she have PKU?
• Is she hypertensive?
• Medication Exposures
• What medications?
• When was the exposure?
• Environmental Exposures
• Does she work in a preschool and was exposed to parvovirus?
• Is she exposed to high doses of radiation?
• 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
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%
Down syndrome phenotype caused by trisomy 21 Down syndrome phenotype caused by 14;21 translocation
Maternal Diabetes: Reproductive RisksMaternal Diabetes: Reproductive Risks
• 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
• Obstetric• Spontaneous preterm labor• Polyhydramnios• Preeclampsia (15-20%)• Intrauterine growth
restriction• Shoulder dystocia• Cesarean delivery
Caudal Regression Syndrome
Teratogen ExposureTeratogen Exposure
<17 days None, “ALL or NONE”
15-25 CNS
20-30 Axial skeleton, limb buds, musculature
25-40 Eyes, heart, lower limbs
56 Organogenesis complete
>60 Fetal growth
• Examples:• Accutane• ACE inhibitors• Lithium• Antiepileptic drugs (AEDs)• Anticoagulants: warfarin• Antidepressants• Methotrexate• Thalidomide
Teratogen ExposureTeratogen Exposure
• 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.
6
n n
= MR = asthma = TSC
2 2
Fetal Ultrasound Showing Cardiac Rhabdomyoma
Fetal MRI Showing Tubers
Prenatal Findings Consistent with Tuberous Sclerosis Confirmed as Neonate
Screening for Genetic DiseaseScreening 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%
Gaucher’s disease 1/900 1/15 95%
ACOG Committee Opinion Number 298, August 2004
Testing and screening options should be made available to all pregnant women
Prenatal Screening & TestingPrenatal Screening & Testing
WhenWhen ScreeningScreening(risk estimate)
DefinitiveDefinitive
(Invasive)(Invasive)
First First TrimesterTrimester
FIRST screen*
Ultrasound CVS
Second Second TrimesterTrimester
Maternal Serum Screen*
Ultrasound
Amnio
Cordo
*First and Second Trimester Integrated and Sequential Screening
Test PerformanceTest 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:Goals in Prenatal Screening:
High sensitivity - low false positive rate
Wide availability
Reproducibility and accuracy
– Human error, testing conditions
First Trimester ScreeningFirst Trimester Screening
• 11-13 6/7 weeks (CRL 39-79 mm)
• Maternal serum sample for PAPP-A and Free -HCG
• Ultrasound for Nuchal translucency
• Detection Rates:
• 80% for Trisomy 21
• 90% for Trisomy 18
• Does not screen for NTDs
PAPP-A -HCG
T21
T18
Increased NT vs Cystic HygromaIncreased NT vs Cystic Hygroma Increased NT > 95th%
– With or without septations Structural defects
– Heart defects most common Syndromic associations Chromosomal defects
– Exponential increase with increased NT
– 50% Down syndrome– 25% Trisomy 13 or 18– 10% Turner Syndrome– 5% Triploidy– 10% other
NT > 3 mm is ABNORMAL
Second Trimester Serum Screening: Second Trimester Serum Screening: Chromosome AbnormalitiesChromosome Abnormalities
• Maternal Serum Screening
• 15-20 weeks
• Triple screen: 60% for T21
• Quad screen: 70% for T21
• Gestational Age Dependent**
• Targeted Ultrasound
• 50% aneuploid fetuses will have ultrasound markers
AGE +AFP +hCG +uE3 +InhA
DR
at
5% F
PR
100
80
60
40
20
0
2nd trimester
single double triple quadruple
76%
30%37%
59%
69%
42%
66%
74%81%
Serum Screening Test Performanceat a fixed 5% False Positive Rate (Dating by Ultrasound)
Wald et al. 2000Malone et al. 2005
Prediction
SURUSS
FASTER
Second Trimester Serum Screening: Second Trimester Serum Screening: Neural Tube Defects Neural Tube Defects
• Neural Tube Defects
• Spina Bifida
• Anencephaly
• AFP increased in “open” defects
• Sensitivity
• 90% anencephaly
• 80-85% open spina bifida
• False positive – 3-4%
Interpreting a Quadruple ScreenInterpreting a Quadruple Screen
AFP HCG/ Inhibin
uE3
T21
T18
NTD
SLO
Bottom Line: AFP is increased with NTDs and decreased with chromosome abnormalities
Elevated MSAFPElevated MSAFP
• Incorrect Dates – most common reason
• Multiples
• Congenital Nephrosis
• Ventral Wall Defects
• IUFD
• Adverse Pregnancy Outcomes
• Stillbirth
• Placental abruption
• Preterm labor
• Oligohydramnios
• IUGR
Ultrasound detection of aneuploidy
0%10%20%30%40%50%60%70%80%90%
100%
Trisomy21
Trisomy18
Trisomy13
Detection rates
Nuchal Fold
CPC
Duodenal atresia Pyelectasis
Clinodactyly
Second trimester sonographic markers of Down syndrome
AV Canal
Trisomy 18Edward 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 13Patau 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 UltrasoundFetal Anatomy by Ultrasound
• Routinely offered with prenatal care
• Performed in the second trimester
• 18-20 weeks optimal
• Basic guidelines
• Level of performance dependent upon
• Who performs the scan
• Where the scan is performed
• Level of equipment
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
GastroschisisGastroschisis
NTDsNTDs
• 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
• One month prior to conception and throughout first trimester
• Decrease recurrence by up to 70%
Lemon Sign Banana Sign
Meningomyelocele Sac Meningomyelocele Sac on Newborn
PGD: Preimplantation Genetic DiagnosisPGD: Preimplantation Genetic Diagnosis
Pearls for Invasive TestingPearls for Invasive Testing
• Risk for Sensitization
• Mom Rh negative – Rhogam
• Other antibodies may increase risk
• Risk for Infection transmission
• Hepatitis B
• Hepatitis C
• HIV
• Need to know familial mutations prior to performing invasive testing
Chorionic Villus SamplingChorionic Villus Sampling• Performed 10-14 weeks
• Does not test for ONTD
• Technique – “Placental biopsy”
• Transabdominal
• Transcervical
• Risk for limb reduction defects if performed < 9 weeks
• Loss rate 1/100-1/200
• Risk for mosaicism (~1%)
TranscervicalTranscervical
CVSCVS
TransabdominalTransabdominal
Performed at 10-14 weeksPerformed at 10-14 weeks
AmniocentesisAmniocentesis
• > 15 weeks
• Loss rate 1/200 (probably closer to 1/300-1/500)
• Tests for ONTD
• Technique
• Fine gauge needle
• Ultrasound guidance
• Aspiration of 20-30 cc of fluid
PERFORMED ROUTINELY 15-20 WEEKSPERFORMED ROUTINELY 15-20 WEEKSUltrasound Guided ProcedureUltrasound Guided Procedure
AMNIOCENTESISAMNIOCENTESIS
CordocentesisCordocentesis
• Percutaneous Umbilical Blood Sampling
• Loss rate 1/100-1/200
• Typically done after 18 weeks
• Ability for:
• Rapid karyotype
• Blood/platelet counts
• Direct fetal injections/transfusions
Fetal Blood SamplingFetal Blood Sampling““PUBS”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.