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PRENATAL DIAGNOSIS
By Dr. JY Ho (Manipal)
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REFERENCES
Hacker & Moore. Essentials of Obstetrics & Gynaecology
5th Edition, 2010.
Royal College of Obstetrics & Gynaecology (RCOG)
Guidelines.
Medscape. Prenatal Diagnosis : Congenital
Malformations and Genetic Disorders, 2011.
http://www.who.int/whosis/mort/profiles/mort_wpro_mys_
malaysia.pdf. WHO Mortality Country Fact Sheet 2006.
American College of Obstetricians and Gynecologists(ACOG). Screening for fetal chromosomal abnormalities.
Washington (DC): American College of Obstetricians and
Gynecologists (ACOG); 2007 Jan. 11 p. (ACOG practice
bulletin; no. 77).
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INTRODUCTION
Congenital anomalies account for 20-25% of
perinatal deaths worldwide.
In Malaysia, congenital anomalies account for13% of neonatal deaths (WHO Mortality Country
Fact Sheet 2006)
Prenatal diagnosis employs various non-invasiveand invasive techniques to determine the health
or any abnormality in an unborn fetus
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BENEFITS OF PRENATAL
DIAGNOSIS
Determines outcomes of pregnancy
Helpful for couples to decide whether tocontinue pregnancy
Indicates possible complications that canarise at birth process
Helpful for managing remaining weeks of
pregnancy
Prepares the couples for the birth of a child
with an abnormality
Helpful for the improvement of the outcomesof pregnancy using fetal treatment
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PREREQUISITES OF PRENATAL
DIAGNOSIS
Pregnant woman > 35years
A previous child or family history of birth defects,
chromosomal anomaly or genetic disorder
A previous child with mental retardation Multiple fetal losses
Abnormal serum marker screening results
Consanguinity
Maternal conditions predisposing to fetalabnormality
Teratogenic exposure
Suspected abnormal ultrasound findings
A parent who is a known carrier of genetic disorder
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TECHNIQUES
NON-INVASIVE
INVASIVE
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NON-INVASIVE TECHNIQUES
Fetal visualization Ultrasound
Fetal echocardiography
MRI
Radiographs
Screening for neural tube defects (NTDs)
Maternal serum -fetoprotein (MSAFP)
Screening for fetal Down syndrome
MSAFP, maternal unconjugated estriol, maternal
serum -hCG, serum inhibin A
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Separation of fetal cells from mothers
blood
Assessment of fetal-specific DNA
methylation ratio
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ULTRASOUND TVS/TAS
Harmless to both fetus and mother
Developing embryo can be visualized at 6 wks gestation
TVS :
- accurate dating, fetal location & number, nuchal
translucency
- cervical length in mid-trimester (identify risk of preterm
delivery
- placental location in 2nd or 3rd trimester
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TAS :
- 16-20weeks structural abnormalities
- 3rd trimester fetal growth (fetal biometry), amniotic
fluid index
- biophysical profile (risk of fetal death within a week
following BPP score of >8 is less than 1%)
Doppler : umbilical & fetal middle cerebral artery
Guide invasive sampling
amniocentesis, chorionic villus sampling, cordocentesis, fetal
biopsies
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FETAL ECHOCARDIOGRAPHY
Can be performed at 15 weeks gestation & beyond
Can identify major structural cardiac defects and
rhythm disturbances with duplex or colour flow
doppler
Recommended when cardiac defects are suspected:
y Identification of extracardiac malformations on routine
ultrasound
y Family history of congenital heart disease
y Suspected genetic disease or fetal chromosome
abnormality associated with heart defects
y Exposure to potentially teratogenic agents
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SCREENING TESTS
MSAFP Triple Test -hCG +
PAPP-A
Nuchal
Translucency
Time (Wks) 15-18 15-18 10-14 11-14
Observation MSAFP&UE3
-hCG
-hCG PAPP-A
Nuchal thickness 3mm
Anomaly to
Detect
Open
NTD
Downs syn Downs syn Downs syn
Test
Sensitivity
Rate
65% 60% 65% 70%
False
PositiveRate
3-5% 5% 5% 5-6%
Inhibin A serum level in Downs syndrome
MSAFP : maternal serum -fetoprotein UE3 : maternal unconjugated estriol
-hCG : maternal -human chorionic gonadotropin
PAPP-A :pregnancy-associated plasma protein A
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SEPARATION OF FETAL CELLS FROM
MOTHERS BLOOD
Fetal blood cells make access to maternal
circulation through placental villi
Can be collected at 18 weeks gestation
Can be analyzed for the diagnosis of genetic
disorders using molecular genetic techniques by
isolating DNA and amplifying it by PCR
Successfully used in the diagnosis of cystic
fibrosis, sickle cell anemia and thalassemia in
fetus
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INVASIVE TECHNIQUES
Fetal visualization
- Embryoscopy
- Fetoscopy
Fetal tissue sampling
- Amniocentesis
- Chorionic villous sampling (CVS)
- Cordocentesis (Percutaneous Umbilical BloodSampling-PUBS)
Preimplantation genetic diagnosis (PGD)
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Cytogenetic investigations
Detection of chromosomal aberrations
Fluorescent in situ hybridization
Molecular genetic techniques
Linkage analysis using microsatellite markers Restriction fragment length polymorphisms
(RFLPs)
Single nucleotide polymorphisms (SNPs)
DNA chip
Dynamic allele-specific hybridization (DASH)
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EMBRYOSCOPY
Performed in the 1st
trimester
A rigid endoscope is inserted via the cervix in
the space between amnion and chorion, understerile conditions & USG guidance to
visualize the embryo for diagnosis ofcongenital malformations
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FETOSCOPY
Performed in the 2nd
trimester
A fine caliber endoscope is inserted into the
amniotic cavity through a small maternal
abdominal incision, under USG guidance
Visualize fetus for structural abnormalities
Also used for fetal blood and tissue sampling
3-5% risk of miscarriage
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AMNIOCENTESIS
Performed between 14-20 weeks
22-gauge needle is passed through motherslower abdomen into clear pocket of amniotic
fluid under USG guidance
10-20ml of amniotic fluid obtained
0.5-1.0% fetal loss and maternal Rh
isoimmunization (anti-D Ig given to Rh vemothers)
Amniotic cells require 1-2 weeks culture forchromosomal analysis
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Genetic diagnosis
- diagnose chromosomal anomalies (trisomy21)
- DNA amplification by PCR allow molecularanalysis of genetic disorders (cystic fibrosis,
sickle cell disease)
Biochemical testing- Amniotic fluid -fetoprotein (AFAFP)
- in fetal dorsal / ventral wall defect (NTD,
gastrochisis)
Diagnosis of perinatal infections
- by culture / PCR (CMV,VZV,Parvovirus B19,
toxoplasmosis)
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3rd trimester fetal lung maturity
- phosphatidylgycerol, lecithin-
sphingomyelin ratio
Therapeutic amniocentesis
- polyhydramnios & twin-twin transfusion
syndrome
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CHORIONIC VILLOUS SAMPLING
Performed between 10-12 weeks gestation
Transcervically or transabdominally
A catheter is passed through the cervix or
abdominal wall into uterus under USG guidanceA sample of chorionic villi surrounding the sac is
obtained
Chromosome analysis can be carried out within 3
days
Information obtained is the same as in
Amniocentesis
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ADVANTAGES AND DISADVANTAGES OF
CVS OVER AMNIOCENTESIS
Advantages Disadvantages
Quicker results
Abnormalities can bedetected early
More acceptable decisions
about termination of
pregnancy can be taken(abortion much safer)
Higher risk of miscarriage
(2-3%)
Risk of fetal limb defects
Higher rate of maternal cell
contamination and confined
placental mosaicism leads todiagnostic ambiguity
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CORDOCENTESIS (PUBS)
Features Information obtained
Performed after 16 weeks
A 25 gauge needle is
inserted into the umbilical
cord under USG guidance
Fetal blood is collected from
umbilical vein for
chromosome analysis and
genetic diagnosis
Same as in Amniocentesis
(but more rapid using fetal
leukocyte culture result
available in 3 days)
Fetal anaemia (superseded
by doppler of fetal MCA)
Risk :Fetal loss rate 1%
Chorioamnionitis
Cord hematoma
Thrombosis of umbilical
vessels
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Features Advantages
a technique used to identify
genetic defects in embryos
created through IVF before
pregnancy
for selective transfer and
implantation of pregnancies
into the uterus that are not
affected by a specific genetic
disorder
more acceptable to those
couples who oppose abortions
preventing heritable geneticdisease, thereby eliminating
the dilemma of pregnancy
termination following
unfavorable prenatal diagnosis
Preimplantation Genetic Diagnosis (PGD)
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1ST TRIMESTER SCREENING
Maternal age Fetal nuchal translucency (NT) thickness
Maternal serum -hCG
Pregnancy-associated plasma protein-A (PAPP-A)
Visualization of nasal bone by USG
* Combination of the above :
Increase Down syndrome detection rate to 93%
Women found to have increased risk of aneuploidyshould be offered genetic counselling and option of
CVS / amniocentesis
Hacker & Moore. Essentials of Obstetrics & Gynaecology 5th Edition, 2010.
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2ND TRIMESTER SCREENING
Triple screening tests
- MSAFP
- Maternal unconjugated estriol
- Maternal serum -hCG
Anomaly scanAmniocentesis
- AFAFP
- Acetylcholinesterase (present only in open NTD)
* MSAFP detect 80-85% of all open NTDs
* Triple screen detect 70% of Down syndrome
* Triple screen + Serum Inhibin A detect 81% of Down syndrome
Hacker & Moore. Essentials of Obstetrics & Gynaecology 5
th
Edition, 2010
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