Prenatal Diagnosis: Significance, Indications and Methods


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.


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


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.


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.


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 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 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.


Thomson and Thomson Genetics in Medicine, 7th Edition
Emery's Elements of Medical Genetics, 14th Edition