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Non-invasive Prenatal Diagnosis: Alternatives to Amniocentesis or Chorionic Villus Sampling

written by: niknak•edited by: Leigh A. Zaykoski•updated: 3/31/2010

Prenatal testing is routinely offered to pregnant women in many countries to determine abnormalities in the fetus. Prenatal diagnosis allows women to make informed decisions about whether to continue with a pregnancy. However, up until recently, testing involved invasive methods that carry a risk.

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    Amnoicentesis and Chorionic Villus Sampling

    The standard method of testing required a sample of fetal cells taken directly from the uterus, either by chorionic villus sampling (CVS) or amniocentesis. The major limitation of these techniques is that they are invasive procedures that carry a small risk of miscarriage (around 1%), and for this reason, many women decide against this form of testing. Therefore. it has been a goal of researchers to find a method of non-invasive prenatal diagnosis (NIPD).

    It has long been known that intact cells and DNA from the fetus cross the placenta and enter the mother’s bloodstream. This has provided hope that prenatal diagnosis of genetic defects could be determined by simply taking a blood sample from the mother.

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    Use of Fetal Cells

    Isolation of intact fetal cells has attracted intense research but has been confounded by many problems. The main problem has been their scarcity. In addition, intact fetal cells can persist in the mother’s bloodstream for decades following pregnancy, and could therefore complicate diagnosis of later pregnancies. Highly sensitive technology for analysis of these cells is being developed, but so far most research has focused on the use of fetal DNA.

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    Cell-Free Fetal Nucleic Acid (cffNA)

    The majority of DNA is contained within cells, but small quantities of DNA can be detected in the blood. It is thought to be a result of cell death. This cell-free DNA is highly fragmented (i.e. is made up of short strands of DNA) and is found in both healthy and diseased individuals. DNA from the fetus can be detected reliably after 7 weeks of pregnancy and is quickly lost from the mother’s blood soon after the baby is delivered.

    Developing NIPD using cffNA has been challenging because distinguishing the fetal DNA from the mother's DNA is difficult. This is because:

    • The amount of fetal DNA in the mother’s blood is relatively low, and levels vary between individuals.
    • The mothers own cffNA is present in much greater amounts.
    • Half of the genetic code of the fetus will be identical to the mother.
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    Fetal DNA Markers

    Many studies have concentrated on DNA sequences that are not present in the mother, such as those on the Y-sex chromosome of male fetuses. Research is now aimed at finding fetal specific ‘markers’ independent of sex or other diagnostic tests: exploiting the differences in gene activation between mother and fetus is one possibility. For example, some genes involved in growth and development may be silent in adults but active in the growing fetus. Two genes, mapsin and RASSFIA have recently been shown to exhibit this difference, providing the first truly specific, universal markers for fetal DNA.

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    Sex Determination, Single Gene Disorders and Rhesus Reactions

    Complete fetal genotyping is not possible from cffDNA in the maternal bloodstream. However cffDNA can be used for the determination of sex, single gene disorders, rhesus blood group incompatibilities and aneuploidy:

    • Sex determination: this has been employed when a male fetus is at risk of a sex-linked genetic disease such as hemophilla or muscular dystrophy.
    • Detection of single gene disorders: so far diagnosis by NIPD is limited to the detection of alleles not detectable in the mother. Fetal DNA in the maternal circulation is made up of small fragments and so not all mutations are detectable. So far it has been used to detect Huntington’s disease, Achondroplasia and Muscular dystrophy.
    • Rhesus blood group incompatibilities: mothers at risk of Rhesus reactions are usually treated with anti-D antibody during the later stages of pregnancy and immediately after birth. However, if the rhesus status of the fetus could be determined by NIPD, this treatment could be avoided for some mothers.
    • Detection of Aneuploidy: abnormalities of chromosome number usually result from a failure of the chromosomes to separate properly during cell division. The most common example of this is trisomy 21 (Downs Syndrome).
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    The Use of Cell-free Fetal Nucleic Acid in Maternal Blood for Non-invasive Prenatal Diagnosis, C.Wright & H.Burton. Human Reproduction Update, 2009, Vol 15, P139-151.

    Cell-free Fetal DNA in the Maternal Serum and Plasma: Current and Evolving Applications, N.Avent, T.Madgett, D.Maddocks& P.Soothill. Current Opinion in Obstetrics and Gynecology, 2009, Vol 21, P175-179