GENETIC TESTING IN PREGNANCY: WHAT ARE THE TESTING IN PREGNANCY: WHAT ARE THE OPTIONS? ... •Klinefelter syndrome 47,XXY- 1in 500 males ... •Advantage is lower false positive

Download GENETIC TESTING IN PREGNANCY: WHAT ARE THE   TESTING IN PREGNANCY: WHAT ARE THE OPTIONS? ... •Klinefelter syndrome 47,XXY- 1in 500 males ... •Advantage is lower false positive

Post on 28-Feb-2018

213 views

Category:

Documents

1 download

TRANSCRIPT

  • GENETIC TESTING IN PREGNANCY:WHAT ARE THE OPTIONS?Christy M. Isler, MD

    East Carolina University

  • DISCLOSURE INFORMATIONGENETIC TESTING IN PREGNANCY: WHAT ARE THE OPTIONS?

    CHRISTY ISLER, MD

    I have no financial relationships to disclose

    I will not discuss off label use and/or investigational use in my presentation

  • LECTURE DESCRIPTION

    A review of screening and diagnostic testing for common genetic abnormalities in pregnancy

  • OBJECTIVES

    A review of screening and diagnostic tests for common genetic abnormalities in pregnancy

    1. Discuss conventional genetic screening tests used in the first and second trimester

    2. Discuss genetic testing with cell free fetal DNA test

    3. Discuss diagnostic genetic testing and the associated invasive procedures

    4. Discuss first and second trimester ultrasound markers for aneuploidy

  • INDIVIDUALIZED RISK

    Every woman has the right to pursue or decline screening or diagnostic tests

    Discuss individualized risk

    Beyond low risk versus high risk

    Counseling re: aneuploidy screening,

    Benefits and risks of diagnostic and screening test

    How accurate are the tests

  • CHROMOSOMAL ABNORMALITIES

  • CHROMOSOMAL ABNORMALITIES

    Aneuploidy

    Triploidy

    Mosaicism

    Abnormal structures

    Deletions/duplications

    Translocations

  • CHROMOSOMAL ABNORMALITYPREVALENCE

    Live births: 1 in 150

    Early embryonic death 60-70%

    First trimester miscarriage 50%

    Stillbirths 5%

    Most common autosomal trisomy

    Down syndrome

    Most common sex chromosome aneuploidy

    Klinefelter syndrome 47,XXY- 1in 500 males

    Turner syndrome 45,X

  • ANEUPLOIDY RISKS FACTORS

    Increasing maternal age

    Prior affected child

    Not increased with 45,X or 47,XYY

    Parental translocationpicture of karyotype

    + screening test

    Ultrasound abnormalities

  • DOWN SYNDROME

    Most common form inherited intellectual disability

    1 in 800 live births

    95% nondisjunction

    Remainder translocation or mosaicism

    40% fetal loss between first trimesterterm

  • WHY IS MATERNAL AGE NOT ENOUGH?

    Maternal age >35 years = 22% detection rate Down syndrome

  • WHICH TEST TO CHOOSE?

    Desire for information

    Prior obstetrical history

    Family history

    Number of fetuses

    Gestational age at presentation

    Available NT services

    Are measurements obtained

    Test sensitivity and specificity

    Cost

    Care of an affected child

    Options for pregnancy continuation

  • TRADITIONAL OR CONVENTIONALSCREENING TESTS

    FIRST

    SECOND

    COMBINED

  • FIRST TRIMESTER SCREENING

    ANALYTES

    Serum HCG (free Beta or total) AND PAPP-A

    NUCHAL TRANSLUCENCY

    CRL 45mm - 84mm

    Maternal age, prior aneuploidy, weight, race, #fetus

    Detection rate 82-87%, screen positive rate 5%

    11 weeks optimal Down syndrome detection

  • NT US

    1. NT margins are clearly visualized

    2. Fetus in a midsagittal plane

    3. Appropriate imaged magnification

    4. Fetal neck in neutral position

    5. Visualize amnion separate from NT line

  • NT US

    6. +Calipers used to perform measurements

    7. Proper caliper placement

    8. Calipers perpendicular to long axis of fetus

    9. Measure at widest NT space

  • 2ND TRIMESTER SCREENING

    150-226 (16-18 best for ONTD)

    QUAD Hcg, AFP, dimeric inhibin A, uE3

    PENTA add hyperglycosolated Hcg

    Age, weight, race, diabetes, #fetus

    No special ultrasound

  • COMBINED SCREENING

    Sequential screening Stepwise

    Contingent

    Integrated screening Serum integrated screening

  • SEQUENTIAL SCREENINGSTEPWISE

    1st Analyte + NT

    Low risk

    2nd

    trimester analyte

    Final results

    High risk

    (CVS/

    amnio)CffDNA

  • SEQUENTIAL SCREENINGCONTINGENT

    1st Analyte + NT

    Low risk

    Done

    High risk

    Diagnostic

    (CVS/amnio)CffDNA

    Intermediate

    2nd trimester analytes

  • INTEGRATED SCREENING

    1st analyteand NT

    2nd

    analyte

    High risk

    Amnio CffDNA

  • SERUM INTEGRATED SCREENING

    1st analyte

    2nd analyte

    High risk

    Amnio CffDNA

  • Test Down syndrome

    Detection rate(%)

    Screen

    positive(%)

    Early results? ONTD screen? NT US?

    First trimester

    screen

    82-87 5 Yes No Yes

    Second

    Trimester

    screen

    81 5 No Yes No

    COMBINED TESTS

    Sequential -

    stepwise

    95 5 Yes Some Yes

    Sequential

    Contingent

    88-94 5 Yes Yes Yes

    Integrated 96 5 No Yes Yes

    Serum

    integrated

    88 5 No Yes No

  • 1ST AND 2ND TRIMESTER SCREENING

    ADDITIONAL BENEFITS

  • 1ST TRIMESTER SCREENING

    Increased NT >3.0mm or >99th centile OR cystic hygroma

    Genetic syndromes

    Isolated anomalies

    Heart

    Abdominal wall

    Diaphragmatic hernia

    Offer genetic testing, ultrasound, fetal echocardiogram

  • UNEXPLAINED ABNORMAL ANALYTES

    Abnormal analytes with no structural anomalies Elevated hCG Elevated AFP Elevated dimeric inhibin A

    Increased risk fetal death IUGR Preeclampsia

    Low maternal serum estriol Smith-Lemli-Opitz syndrome Placental steroid sulfatase deficiency

  • CELL FREE FETAL DNANIPT

    NIPS

  • CELL FREE FETAL DNA

    Short segments of DNA in maternal blood

    Released from placental cells undergo apoptosis

    Cleared from maternal circulation within hours of childbirth

    Multiple methods-performance similar

  • CELL FREE FETAL DNADETECTION

    Down syndrome 99% detection rate

    Screen + rate 0.5% (women with reportable results)

    Advantage is lower false positive rate with less invasive procedures

    Detection lower for other aneuploidies

    Trisomy 18 97%

    Trisomy 13 87%

    Sex chromosome abnormalities

  • CELL FREE FETAL DNALOW FETAL FRACTION

  • CELL FREE FETAL DNAPOSITIVE TEST

    Fetal aneuploidy

    Confined placental mosaicism

    Resorbing twin

    Maternal malignancy

    Maternal aneuploidy

  • CELL FREE FETAL DNAPOSITIVE PREDICTIVE VALUE

    Age Age-related risk PPV

    20 1 in 804 79%

    30 1 in 526 86%

    40 1 in 57 98%

    Risk for Down syndrome

    All drawn at 12 weeks

  • NT WITH CELL FREE FETAL DNA TEST

    Even if conventional analytes not used, there can be a benefit

    Increased NT >3.0mm or >99th centile OR cystic hygroma

    Genetic syndromes

    Isolated anomalies

    Heart

    Abdominal wall

    Diaphragmatic hernia

  • DIAGNOSTIC PROCEDURESChorionic villus sampling

    Amniocentesis

  • CVS Amniocentesis

    Timing 10-13 weeks >15 weeks

    Complications if too early Limb reduction defects Clubbed foot, culture failure

    Pregnancy loss 1 in 400 1 in 400

    Same complication rate Transabdominal vs

    transvaginal

    Transplacental or not

  • KARYOTYPE

    Metaphase analysis of cultured cells

    Results in 7-14 days

    Detects >99% of aneuploides

  • MICROARRAY

    Whole genome SNP-based copy number microarray

    >2.5 million genomic sites

    Cultured or uncultured cells

    Can be used on nonviable cells

    Fetal death/stillbirth

  • DIAGNOSTIC GENETIC TESTS

    Karyotype Microarray

    Aneuploidy X X

    Triploidy X

    Small deletions/duplications X

    Large deletions/duplications X X

    Translocations/Inversions X X

    Balanced rearrangements X

    Low level mosaicism

    Uniparental disomy X

    Homozygocity X

  • DIAGNOSTIC TEST CHOICE

    Abnormal ultrasound and normal karyotype

    6% have abnormal microarray

    Normal ultrasound and normal karyotype

    1.7% have copy number variant (+/- pathogenic)

    Test choice

    General

    Anomalies characteristic of particular aneuploidy

    Abnormal screening or cell-free DNA testing

  • FISH-FLUORESCENT IN SITU HYBRIDIZATION

    Fluorescent-labeled probes for specific chromosome regions

    Uncultured cells-results about 2 days

    Common panels Chromosomal 13/18/21/X/Y

    22q11.2 deletion syndrome

    Screening test

    False + and false- possible

  • INVASIVE PROCEDURESWITH MATERNAL INFECTION

    Hepatitis B - limited data

    Vertical transmission dependent on viral load

    Hepatitis B e antigen higher risk

    Hepatitis C - limited data

    Risk appears to be low

    HIV - limited data

    CART treatment/undetectable viral load=?transmission risk

  • ULTRASOUNDSecond trimester

  • ULTRASOUND FOR DETECTION OF ABNORMALITIES

    Major fetal anomaly detection: 84%

    Down syndrome detection: 50-60%

    2014 NICHD Workshop for Fetal Imaging

  • CHROMOSOMAL MARKERSSECOND TRIMESTER

    Thickened nuchal fold

    Mild ventriculomegaly

    Echogenic intracardiac focus

    Pyelectasis

    Echogenic bowel

    Short femur length

  • CHROMOSOMAL MARKERSTHICKENED NUCHAL FOLD

    6mm from outer edge of occipital bone to outer skin in midline

    Likelihood ratio 10-20 Down syndrome

    Detailed ultrasound

    Offer aneuploidy testing

  • CHROMOSOMAL MARKERSMILD VENTRICULOMEGALY

    Lateral ventricular atrial measurement 10-15mm

    Likelihood ratio 25 for Down syndrome

    Detailed ultrasound

    Aneuploid testing

    Cytomegalovirus testing

    Repeat ultrasound 3rd trimester

  • CHROMOSOMAL MARKERSECHOGENIC INTRACARDIAC FOCUS

    Incidence

    Euploid 4%

    Down syndrome 15-30%

    Likelihood ratio 1.5 for Down syndrome

    Isolated-offer aneuploidy screening

    If screening negative, no further evaluation is required

  • CHROMOSOMAL MARKERSPYELECTASIS

    Renal pelvis 4 mm in AP diameter up to 20 weeks gestation

    Likelihood ratio 1.5 for Down syndrome

    Isolated-offer aneuploidy screening

    Repeat ultrasound 3rd trimester

  • CHROMOSOMAL MARKERSECHOGENIC BOWEL

    Fetal small bowel as echogenic as bone

    Likelihood ratio 6 for Down syndrome

    Aneuploidy, intra-amniotic bleeding, cystic fibrosis, cytomegalovirus

    Aneuploidy screening or diagnostic testing

    CF testing and CMV testing

  • CHROMOSOMAL MARKERSSHORT FEMUR LENGTH

    Measure

  • SECOND TRIMESTER ULTRASOUND

    Limits of 2nd ultrasound markers

    Lack of standardization in measurements

    Confounding factors

    High maternal BMI

    Multiple gestation

    Machine quality

    Experience of ultrasonographer

  • MULTIFETAL GESTATION

    Decreased effectiveness of screening

    # fetuses and zygosity

    How does a single aneuploid fetus affect management?

  • MULTIFETAL GESTATION

    NT screen only-9% false positive 75% detection

    Absent nasal bone Found in 69% Down syndrome

    Up to 2.6% of euploid fetus

    Detection by zygocity-5% false positive rate 73% monozygotic

    43% dizygotic

    Cell free fetal DNA limited data

  • CONCLUSION

    Right test

    Right time

    Right patient

    ONE SIZE DOES NOT FIT ALL