Overview:
Streele and Breg in 1966
established that the chromosomal make up of a fetus could be determined by
study of cultured cells from the amniotic fluid. Due to the well-known
association between the advanced maternal age and an increased risk of Down
syndrome, the role of prenatal diagnosis as a medical service was of utmost
importance.
Definition
Prenatal diagnosis in simple term
indicates the ability to detect abnormalities in an unborn child.
Goal and significance
The main goal of prenatal
diagnosis is to inform couples about the risk of birth defect or genetic
disorder in their pregnancy and to provide them with informed choices on how to
manage that risk.
Indications for prenatal
diagnosis:
Advanced maternal age
Due to the well-known association
of advanced maternal age with increased risk of having a baby with Down
syndrome and the other autosomal trisomy syndromes, advanced maternal age has been the most
common indication to be considered for prenatal diagnosis.
The age of 35 years and onward at the expected date of delivery is usually
considered as advanced maternal age to offer prenatal diagnosis by invasive
methods (like amniocentesis and chorionic villus sampling). The reason to
consider this age is probably the risk, at 35 years, of having a fetus with a
chromosome abnormality is thought to be equal to the risk of miscarriage
associated with amniocentesis (approx. 1 in 250).
Previous child with a chromosome
abnormality
Despite having the normal
chromosomes themselves, the parents of a child with chromosomal aneuploidy are
at increased risk of having chromosomal abnormality in a subsequent child. For example
a woman at 30 years of age with previous child having Down syndrome has a
recurrence risk for any chromosomal abnormality of about 1/100, compared to the
age-related population risk of about 1/390.
Family history of a chromosome
abnormality
Prenatal diagnosis for a couple
is often indicated if there is a family history of chromosomal abnormality,
most commonly Down syndrome. For most couples generally the risk is no greater
than that for the general population. This is because most cases of trisomy 21
or other chromosomal abnormality will have arisen as a result of
non-disjunction rather than as a result of a familial chromosomal translocation
or other rearrangements.
Presence of a structural
chromosome abnormality in one of the parents
In such case, the type of
chromosomal abnormality and sometimes the parent of origin determine the risk
of having anomaly in a child. The greatest risk, 100% for Down syndrome, occurs only if either
parent has a 21q21q Robertsonian translocation or isochromosome.
Family history of a single-gene
disorder
For a positive family history for
single gene disorder (or if prospective parents have already has an affected
child or if one of the parents is affected) that bears a significant risk to
offspring (recurrence risk 25% to 50%), the prenatal diagnosis is strongly
indicated. Prenatal diagnosis is generally carried out by either biochemical or
DNA analysis for a large number of single-gene disorders.
In case of family history of an
X-linked disorder for which there is no specific prenatal diagnostic test, the
parents of a boy affected with an X-linked disorder may use fetal sex
determination to help them decide whether to continue or to terminate a
subsequent pregnancy because of the high recurrent risk (25%) associated with
it.
Family history of a neural tube
defect
Because of the high risk of
having a child with a neural tube defect (NTD), prenatal diagnosis is indicated
for first-degree relatives (and often second-degree relatives) of patients with
NTDs. Ultrasonographic examination of the fetus along with assay of maternal
serum alpha fetoprotein (AFP) can be used as non-invasive method (instead of
invasive amniocentesis) of prenatal diagnosis to detect NTD.
Family history of other
congenital structural abnormalities
In such cases, a careful
evaluation of the pedigree is helpful to determine the risk associated with
each pregnancy. If the risk to a pregnancy is increased , detailed
ultrasonographic examination looking for the specific structural abnormality
can be offered at around 16-18 weeks’ gestation.
Abnormalities identified in
pregnancy
Any abnormalities identified
during pregnancy by prenatal diagnostic screening procedures, such as triple
testing and fetal anomaly scanning, requires invasive prenatal diagnostic
methods like amniocentesis and chorionic villus sampling for further
confirmation.
Other high-risk factors
These include:
Parental consanguinity, as it is
associated with an increased risk that a child will have a hereditary disorder
or congenital anomaly.
A history of recurrent
miscarriages or a previous unexplained stillbirth is also associated with
increased risk of problem in a future pregnancy. A history of three or more
unexplained miscarriages requires parental chromosome analysis to exclude a
chromosomal rearrangement such as a translocation or inversion.
Methods of Prenatal diagnosis
Invasive techniques
Amniocentesis
Procedure: Amniocentesis is an
invasive technique of prenatal diagnosis in which 10-20 ml of amniotic fluid is
aspirated trans-abdominally by syringe under ultrasonographic guidance. The
fluid is centrifuged to separate fetal cells from the fluid. The cells are then
cultured and grown (which takes at least 14 days) to perform chromosomal or DNA
analysis to detect any abnormalities.
In addition to fetal chromosome and
DNA analysis, the concentration of alpha-fetoprotein (AFP) can be evaluated in
amniotic fluid to detect neural tube defects (NTDs).
Optimal time: This procedure is performed
at 15th to 16th week of gestation. However, the procedure
can be performed at a much earlier stage in pregnancy like between 10th
to 14th week of gestation but with increased risk to fetal outcomes.
Risk and complications: The amniocentesis
is associated with 0.5-1% risk of miscarriage (the same risk is approximately
1% to 2% for any pregnancy at this stage of gestation). Other complications are
rare, including leakage of amniotic fluid, infection, and injury to fetus by
needle puncture. In case of early amniocentesis, the risks are
increased as well as it is also associated with clubfoot (talipes equinovarus).Besides, if the result
is abnormal, it may lead to possibility of having to consider a mid-trimester
termination of pregnancy by an induction of labor.
Chorionic villus sampling (CVS)
Procedure: chorionic villus
sampling (CVS) is also an invasive technique involving the aspiration of
chorionic villi (CV) tissue through trans-cervical or trans-abdominal route
under the USG guidance. Chromosomal analysis can be done on CV tissue either
directly (in which case a provision diagnosis can be obtained within 24 hours)
or following a culture. The tissue can also be used for prenatal diagnosis by
biochemical assay or DNA analysis.
Optimal time: CVS is usually
carried out at 11 to 12 weeks of gestation. Thus, CVS gives opportunity to make
a first trimester prenatal diagnosis.
Risk and complications: it is associated with increased risk of
miscarriage of 1-2%. If performed before 9 to 10 weeks of gestation, it is also
found to be causing limb abnormalities in the embryo. Maternal contamination of tissue and confined placental mosaicism
may also complicate the result.
Cordocentesis:
In this procedure, fetal blood sample is obtained from one of the umbilical vessel in the umbilical cord generally under the USG guidance through trans-abdominal route.
Optimal time: 19-21 weeks of gestation.
Risk and complication: associated with 1-2% risk of fetal loss.
Ultrasonography:
Besides being used for
obstetric purpose (like placental location and multiple pregnancies), USG can
be a valuable tool for prenatal diagnosis as it can detect the structural
anomalies that are not associated with chromosomal, biochemical or molecular
defects.
Advantage: it is a
non-invasive method and presents no known risk to fetus or mother.
Optimal time: a
routine and detailed USG scanning for fetal anomaly is advised to all pregnant
women at around 16 to 18 week of gestation as
a screening procedure for structural abnormalities such as neural tube
defects or cardiac anomalies. USG can also be very useful in detecting
chromosomal abnormality as suggested by certain features. For example,
increased nuchal translucency (as the measure of nuchal thickness) in the first
and second trimester is more likely to be associated with Down syndrome and /or
cardiac anomaly. Such finding would lead to fetal karyotyping for definitive
chromosomal analysis.
Fetoscopy:
Fetoscopy is the
process of visualization of fetus by using a endoscope. Though superseded by
detailed USG, occasionally this method is used during second trimester to
detect the presence of subtle structural abnormalities. It has also been used
to obtain the fetal tissue samples that can be analyzed to detect several rare
disorders. For example, it can be done for epidermolysis bullosa, an inherited
skin disorder and for metabolic disorders for which the enzymes are expressed
only in certain tissue or organs like liver.
Risk and Complication: it
presents relatively higher risks of about 3-5% for miscarriage.
Radiography:
Radiography has been used in the
past to diagnose inherited skeletal dysplasias. It is almost obsolete now
because of the dangers of radiography to the fetus and the widespread
availability of detailed ultrasonography.
References
Thomson and Thomson Genetics in Medicine, 7th Edition
Emery's Elements of Medical Genetics, 14th Edition
References
Thomson and Thomson Genetics in Medicine, 7th Edition
Emery's Elements of Medical Genetics, 14th Edition