prenatal diagnosis · prenatal diagnosis includes all aspects of embryonic and fetal diagnosis ......
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PRENATAL
DIAGNOSIS Marzena Wiśniewska M.D.,Ph.D.
Chair and Depart. of Medical Genetics
Prenatal diagnosis
includes all aspects of embryonic and fetal
diagnosis
is indicated in about 8% of all pregnancies
At least 93% of prenatal tests provide
reassurance for the couple concerned, and
selective termination of pregnancy is
indicated in less than 7%
Prenatal diagnosis
It is important to outline to the couple the
limitations of the appropriate test or tests
and to remind them that no single test or
even combination can exclude all
abnormalities !
Identification of at risk
pregnancies
Factors identifiable prior to a pregnancy:
elevated maternal age
parental consanguinity
ethnic origin
maternal illness or medication
positive family history
population carrier screening
Identification of at risk
pregnancies
Factors identifiable during pregnancy:
abnormal ultrasound appearance
alphafetoprotein screening
other biochemical screening tests
polyhydramnios, oligohydramnios
maternal exposure to teratogens
Termination of pregnancy after prenatal
diagnosis
(22 genetic centers, Canada)
22222 women had indications for prenatal diagnosis
17599 women decided to have invasive prenatal diagnosis (79%).
Chromosome aberrations were found in 399 fetuses (2.2%)
184 women decided to have termination of pregnancy (1% from 17599)
Techniques for prenatal diagnosis
Non-invasive
Invasive
Non-invasive techniques
Ultrasound (USS).
Maternal serum screening
Fetal cells in the maternal circulation
(NIPT)
Magnetic resonance imaging (MRI) of the
fetus
Invasive techniques
Amniocentesis
Chorionic villus sampling and placental
biopsy
Cordocentesis
Fetoscopy
ULTRASOUND SCANNING (USS)
ULTRASOUND
First used as a method of prenatal diagnosis
in 1972 for anencephaly
Quality depends on experience of the doctor
and quality of the ultrasonograph
It can detect many major structural
anomalies , but not all, e.g. cleft palate
USS - application
Screening procedure (done in every
pregnant women) in 11, 20, 30 weeks
gestation
Detailed ultrasound is used when there are
risks for specific anomalies
USS 11-13 weeks gestation
Dating of pregnancy
Determining fetal viability
Detection of number of fetuses
Early diagnosis of major anomalies
Nuchal scanning (nuchal translucency, NT)
Nuchal translucency 11-13+6
weeks gestation
Subcutaneous accumulation of fluid at the back of the fetal neck is visualized by USS as increased nuchal translucency (NT) thickness (Nicolaides, 2004).
The NT thickness grows together with time of pregnancy and crown-rump length
After 14 week it is much more difficult to measure nuchal translucency
NT in 11-13+6 weeks gestation 95%
transabdominal
probe
5% transvaginal
probe
Crown – rump length 45-84 mm
NT - interpretation
NT thickness is associated with chromosomal abnormalities, wide range of cardiac defects and genetic syndromes
Nuchal scanning can identify more than 75% fetuses with Down syndrome (false positive results are 5%).
During the second trimester NT is usually absorbed, but in some cases it changes into nuchal edema lub cystic hygroma.
Kariotype of
fetus
No of cases NT>95 centile
normal 95 476 4 209 (4,4%)
Trisomy 21 326 234 (71,2%)
Trisomy 18 119 89 (74,8%)
Trisomy 13 46 33 (71,7%)
Turner s. 54 47 (87%)
Triploidy 32 19 (59,4%)
Others 64 41 (64,1%)
Total 96 127 4 767 (5%)
Other causes of increased nuchal translucency
thickness...
Single gene disorders (~100 syndromes)
Fetal cardiac insufficiency associated with heart defect and/or defect of big vessels
Venostasis of head and neck of the fetus due to compression
Abnormal or delayed development of lymphatic system
Abnormal lymphatic drainage in neuromuscular diseases of the fetus
Fetus anaemia or hypoproteinemia
Infections of the fetus causing anaemia or circular insufficiency
Changes of intercellular substance
Ultrasound markers typical for
trisomy 21
USS markers LR for isolated markers
Shortening of humerus 4,1
Shortening of femur 1,6
Hydronephrosis 1,0
Hyperechogenic place in
heart
1,1
Hyperechogenic intestine 3,0
Big defects 5,2
Nasal bone
Another good ultrasound marker of Down
syndrome is agenesis or hypoplasia of nasal
bone of the fetus – NB
NB (+), agenesis is described as NB(-).
67 % fetus with trisomy 21
55 % fetus with trisomy 18
34 % fetus with trisomy 13
11 % fetus with monosomy X
Congenital defects are markers
of chromosome abnormalities
The more defects are detected of the fetus
the higher risk of having chromosome
aberrations is observed
2 congenital defects – risk approx 10%, 3
defects – 30%, 4 defects – 50%, 5-7 defects
– 60-70%, 8 or more – approx 90%.
Congenital heart defects
Intestinal obstruction
X-ray with contrast
done after birth
Duodenal atresia
frequency 1/5000
40% in chromosome
abnormalities (trisomy 21)
Omphalocoele
frequency 1/3000
60% in chromosome
aberrations
Polycystis kidneys
Autopsy view
USS – new methods
Three- dimensional USS (3D).
Doppler assessment of flow and
echocardiography used in diagnosis of the
fetal heart
USS – 3D technique
Simian crease
4D - USS
Maternal serum screening
Involves the use of the unique fetal markers,
proteins made by the fetus during pregnancy
Alpha-fetoprotein (AFP)
Human chorionic gonadotrophin (beta-hCG)
Unconjugated estriol (uE3)
Inhibin A
PAPP-A (pregnancy-associated plasma protein
A)
First trimester screening
beta- hCG
PAPP-A
Pregnancy with trisomy 21 in 12 week:
beta-hCG
PAPP-A
False positive 5%
False negative 40%
Chromosome
Aberration
beta-hCG
PAPP-A
Trisomy 13
Trisomy 18
Aberration of sex
chromosome
Normal
First trimester screening + NT
measure For trisomy 21 – detection 86.3%, false
positive 5%
For all chromosome aberration detection
90%, false negative 6%
Computer complex analysis of the data +
factors such as smoking, age of the mother,
age of the pregnancy, maternal diabetes is
done
If the risk is > 1:300 the invasive methods
are indicated
Second trimester screening
beta-hCG + AFP + u(E3) – triple test
Rate of detection 50-75% pregnancy with
trisomy 21, false positive 5%
Combination of NT improves rate of
detection 85-90%, false positive 5%
Nowadays done quite rare
Fetal abnormalities with
elevated AFP
Open neural tube defects!
Eventration
Lethal skin disorders
Epidermolysis bullosa simplex
Aplasia cutis congenita
AFP AFP
Fetal cells in maternal circulation
1:1000 or 1: 10000 nucleated cells originate
from the fetus
(trophoblast cells, nucleated erythrocytes,
granulocytes).
Non-Invasive Prenatal Test
(NIPT)
DNA płodu
DNA matki
Cell-free fetal DNA
5-15 % pozakomórkowego DNA w układzie krążenia matki stanowi DNA płodu (cff DNA)
The aim of the test
Excluding the most common chromosomal
aberrations.
It is done with maternal blood containing
fetal DNA.
Detection over 99% aneuploidy of
chromosomes 21, 13, 18.
MRI of the fetus
Done in the 1st and in the 2nd trimester
Complementary invastigation to USS
Application: neural tube defects, cancer of the fetus, diaphragmatic hernia, intestinal obstruction
Often necessary before intrauterine fetus therapy
Invasive technique
Chromosome abnormalities
rutine cytogenetic
FISH, MLPA, aCGH
Single gene disorder
molecular diagnosis
AMNIOCENTESIS
Amniocentesis-indications
1. Increased risk of birth of a child with chromosome aberration:
Advanced maternal age (over 35 years old)
Previous child with chromosomal abnormality
Parental chromosomal abnormality (balanced translocations, inversions)
Fetal abnormality suggesting the presence of chromosomal abberation
Low maternal serum alpha-fetoprotein (MSAFP)
Psychologic reasons
2. Increased risk of birth of a child with anencephaly or spina bifida
Standard amniocentesis
15-18 weeks gestation
Risk of complications 1%
Timescale for results: 9 days - 3 weeks
Early amniocentesis is possible to be done
in 10 -14th week of pregnancy, but the risk
of complications is 2%
Chorion villus sampling (CVS)
11-13 weeks gestation
Risk of complications: 1-2%
Timescale for results: 7 days
Procedure of choice of DNA analysis
There is the possibility of causal association
between early CVS and transverse limb deficiency
Transverse limb deficiency due to CVS < 11 week
1/200, >11 week 1/5000 CVS done
Chorion villus sampling
Indications for CVS
The same as for amniocentesis, except increased
risk of birth of a child with neural tube defects
Is a procedure of choice for DNA analysis as
DNA can be extracted directly from trophoblast
sample (fragile X syndrome, DMD, Huntington
chorea, spinal muscular atrophy).
Cordocentesis (PUBS – percutaneous
umbilical blood sampling)
from 18 week of gestation to near term
risk of complications 2%
Cordocentesis - indications
USS detection of fetal abnormalities, suggesting the possibility of chromosomal aberration in the fetus (after the 18th week of pregnancy)
Prenatal diagnostics of blood diseases (haemophilia, beta - thalassemia).
Results’ verification in suspection of chromosomal mosaicism in the fetus on the ground of amniocentesis
Late application to prenatal diagnosis
Complications
Vaginal spotting/bleeding (1-4%) especially after transcervical approaches (TC)
Amniotic fluid leak causing oligohydramnios
TC procedures – intrauterine infection (<0.1%)
Increased risk for respiratory problems after amniocentesis eg.transient tachypnoe of the newborn
The procedure-associated pregnancy loss rate is estimated at 1.5-2%
Fetoscopy
Thank you for your attention