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.