Hanan Hamamy
Department of Genetic Medicine and Development
Geneva University
Training Course in Sexual and Reproductive Health Research
Geneva 2016
While it is never easy for a couple to decide to
pursue prenatal diagnosis because of the
possibility of subsequently having to consider
termination of pregnancy, prenatal diagnosis is
an option that could be chosen by couples at
high risk of having a child with a serious
congenital disorder.
Invasive Non-invasive Preimplantation
Amniocentesis Ultrasonography
Chorion villus Maternal serum
biopsy markers
Fetal blood, Free DNA sampling
other tissues in maternal blood
For most women, prenatal genetic screening involves
a blood test for maternal serum markers and a special
ultrasound done early in pregnancy.
Abnormal results could point to the possibility that
the fetus has:
1. Down syndrome
2. Other chromosomal abnormalities such as Trisomy 18 and Turner syndrome
3. Open neural tube defect (ONTD)
4. Other conditions
Ultrasound offers a valuable means of prenatal
diagnosis. It can be used not only for obstetric
indications, such as placental localization and the
diagnosis of multiple pregnancies, but also for the
prenatal diagnosis of structural abnormalities that
are not associated with known chromosomal,
biochemical or molecular defects.
Ultrasound is particularly valuable because it is non-
invasive and conveys no known risk to the fetus or to
the mother. It does, however, require specialized
expensive equipment and a skilled and experienced
operator.
Spina bifida indicates a defect in the closure of the vertebral
column leading to protrusion of the meninges/spinal cord.
Severe conditions lead to lower limb paralysis and incontinence.
The observation that increased nuchal
translucency (NT) is seen in fetuses who are
subsequently born with Down syndrome, has
resulted in the introduction of measurements
of nuchal pad thickness in the first trimester
as a screening test for Down syndrome.
First trimester risk assessment using the double
test (pregnancy-associated plasma protein A
(PAPP-A) and free beta-human chorionic
gonadotropin (HcG) and nuchal translucency
thickness in combination with maternal age has
been shown to be very efficient giving a
detection rate of 90% for Down syndrome and
for a 5% false-positive rate.
Detailed 'fetal anomaly' scanning is being
offered routinely to all pregnant women at
around 18 weeks gestation as a screening
procedure for structural abnormalities such as
cardiac and other congenital malformations.
Recently, a new screening test based on the
analysis of cell free DNA (cfDNA) on maternal
blood is introduced.
cfDNA testing is a highly effective form of
prenatal aneuploidy screening that can
facilitate early detection as well as early
reassurance.
Currently, cfDNA testing is more expensive
than conventional screening.
This test has an excellent performance in
screening for trisomy 21, with a detection rate
above 99% and a false positive rate lower than
0.1%.
A screening test does not give a yes or no
answer but identifies increased risk for certain
disorders so that definitive diagnostic tests
can be offered.
If the risk is considered high, then diagnostic
tests could be done by obtaining fetal tissues
either through chorion villus sampling or
amniocentesis.
Termination or
Continuation of
pregnancy
Abnormal results
CVS
amniocentesis
Abnormal results
maternal serum markers
Ultrasound
A fundamental difference between prenatal and other
types of screening is that when prenatal screening leads
to the diagnosis of an abnormality in the fetus there is
often no treatment available before birth. Women are
left with the choice between continuing the pregnancy
knowing the infant will be born with the condition
identified or abortion to prevent the birth of an
affected child.
There is diversity of opinion among Islamic
institutions on the issue of pregnancy
termination, ranging from an absolute
prohibition of abortion at any time to
permission for pregnancy termination before
the 120th day of gestation under specific
circumstances.
Ethical, legal and religious issues accepted in
the country make the decision.
Abnormal results in prenatal screening
Previous child with a chromosome abnormality
(probability of translocation carrier in parents)
Family history of a chromosome abnormality
Family history of a single gene disorder
Family history of neural tube defect or other
congenital abnormalities
Done around the 16th week
of gestation
Aspiration of 20 ml of
amniotic fluid through the
abdominal wall under
ultrasound guidance
0.5-1% risk of miscarriage
Usually performed at 11-
12 weeks gestation
Transcervical aspiration of
chorionic villi under
ultrasound guidance
Around 1% risk of
miscarriage
The earlier the amniocentesis is performed,
the higher the risk of amniotic fluid leakage
and the higher the risk for foot deformities.
It is advisable not to perform amniocentesis
before 15 weeks gestation.
CVS should not be performed before 10 weeks
due to the risk of limb reduction defects.
Experienced operators have a higher success
rate and a lower complication rate.
The couple should be counseled by a genetic
counselor to inform them of the test results
and the risks to the fetus.
The couple should take an informed decision
about termination or continuation of pregnancy.
Autonomy of decision is crucial.
The ethical, legal, and religious issues should be
respected.
Many cytogenetic laboratories are capable of
diagnosing chromosome aberrations in fetal cell
cultures whether obtained through amniocentesis or
chorionic villus sampling.
The diagnosis of single gene disorders in fetal cells is
more difficult and requires specialized laboratories
and advanced technology. For less common and rare
disorders, samples have to be sent abroad.
How can congenital disorders be categorized???
1. Severity of disease
2. Survival
3. Impact on family
4. Impact on affected
5. Impact on society and government
Preimplantation Genetic Diagnosis (PGD) uses in vitro
fertilisation (IVF) to create embryos.
Tests one or two cells from each embryo for a
specific genetic abnormality.
Identifies unaffected embryos for transfer to the
uterus.
The approach through PGD assists couples at risk of
an inherited disorder to avoid the birth of an
affected child without going through selective
pregnancy termination.
1. To detect chromosomal disorders by fluorescence in situ
hybridisation (FISH).
2. To identify single gene defects such as cystic fibrosis, where
the molecular abnormality is testable with molecular
techniques after polymerase chain reaction (PCR) amplification
of DNA extracted from single cells.
3. To determine the sex of the embryo for sex linked disorders
where the specific genetic defect at a molecular level is
unknown, highly variable, or unsuitable for testing on single
cells.
*Reference Guide for Health Care Providers
Prenatal Screening Tests for the Detection of: Down Syndrome, Trisomy 18 and Open Neural Tube Defects
http://www.geneticresourcesontario.ca/Provider.pdf
Informed choice - Before ordering the test, discuss
benefits, risks and limitations.
Autonomy - The patient should choose whether to
have prenatal screening.
What prenatal screening options are available in your
area?
What option is most suitable for your patient?
Which test will provide the optimal care for your
patient?
A screening test is not diagnostic.
Prenatal diagnosis can be followed by intrauterine or
neonatal surgery for the correction of certain
congenital anomalies such as cardiac and renal defects.
In utero gene therapy could become a practical
therapeutic option in the future for the treatment of
serious monogenetic diseases.
Prenatal diagnosis with in-utero transplantation offers
the potential to treat a large number of diseases by
transplantation of healthy cells into a fetus with a birth
defect.
Detection rates for first trimester structural
anomalies by ultrasound range from 30% in low
risk, to about 60% in high risk groups.
Screening for chromosomal disorders using
biochemical markers, ultrasonography, and
recently by non-invasive prenatal diagnosis
based on cell-free fetal DNA in maternal
plasma could be offered whenever feasible and
acceptable.
