Wednesday, 9 September 2015

Non-Invasive Prenatal Diagnosis- A Brave New World?

Got his father's eyes

Up to relatively recently the only way to determine whether a pregnancy was chromosomally abnormal was by invasive prenatal testing. A sample of the placenta, or more usually the amniotic fluid within the womb, was taken by the obstetrician and sent to the genetics lab for culture and analysis. In this way, foetal chromosomes (gross genome) could be examined to detect abnormalities, mostly Down syndrome due to an additional chromosome 21. Although screening tests are available to assess a woman’s risk of a chromosomally abnormal pregnancy, the only sure way to determine chromosome status is by sampling the baby's cells. Although prenatal testing is relatively safe, there is always an attendant risk to the pregnancy due to the procedure itself. In a good centre, the risk is low- about 0.3%. Clearly it is not possible to offer all pregnant women invasive testing. Most women will have a very low risk and therefore it makes no sense to offer a pregnant woman with a risk, say in the order of 1 in 2,000, a procedure with an inherent risk of abortion of 1 in 300. Furthermore, there is no way the system could cope if every woman underwent invasive testing. Therefore, screening is necessary and desirable to identify high-risk pregnant women.

Screening is based on measuring biochemical markers in the mother’s blood together with an assessment of foetal anatomical structures. Finally, maternal age is factored in. Combining these independent risk factors gives an aggregate risk which can be expressed as a number, for example, 1 in 200. This represents the risk of carrying a Down syndrome foetus. If the risk reaches a 'high risk' level the woman is offered an invasive diagnostic test. Generally, about 5% of pregnant women are tested. When faced with the prospect of a baby with a clinically significant chromosome abnormality most couples choose the harrowing decision to abort the pregnancy; 90% of Down syndrome pregnancies are voluntary aborted.

Recently a new test has been added to the diagnostic repertoire and enables testing without extracting a sample of amniotic fluid from the pregnancy. This test relies on the presence of foetal DNA in the maternal blood stream.

It has been known since the 19th century that foetal cells can enter the maternal circulation during pregnancy. Wouldn’t it be great if we could isolate these cells from the mother’s blood and use them for prenatal diagnosis? In this way, we could obtain a result without sticking a needle into the womb and thereby eliminate the risk of abortion due to the procedure itself. The problem with this approach is that foetal cells in the maternal circulation occur at extremely low levels. In a typical maternal blood sample, only one foetal cell is present for every million maternal cells. A more serious problem arises due to the persistence of certain types of foetal cells. For instance, foetal T lymphocytes, a type of blood cell, linger in the mother’s blood for years making it difficult to know whether the cells analysed relate to the current or to a previous pregnancy. Therefore, the technical limitations of this approach prevent its introduction into the diagnostic setting.

However, all is not lost and foetal DNA also enters the mother’s blood stream, often in appreciable amounts. Up to 6% of the cell-free DNA in the maternal blood comes from the baby. Also, removal of foetal DNA from the maternal circulation is rapid, so there is no problem with contamination from previous pregnancies.

DNA is the genetic stuff that makes up chromosomes and determines all our genetic traits. It is fairly easy from a technical perspective to isolate foetal DNA and use it to determine whether the baby carries a chromosome or genetic defect. This test has recently been introduced into our laboratory and has the potential to revolutionise prenatal diagnosis.  Like all laboratory tests, it is not without limitations. Although the test is accurate there is a small chance that the result will give rise to a ‘false positive’. In this case, the baby is normal even though the test indicates otherwise. Therefore, all positive cases should have a follow up invasive prenatal test.

In certain instances, analysing foetal DNA from mother's blood will not provide an interpretable result. In cases of twins and where the mother is morbidly obese, the analysis is not accurate. Furthermore, this test provides less diagnostic information than conventional amniotic fluid analysis and 5% of clinically significant chromosome problems will be missed.

It unlikely that the cost of the test, for now, will be covered by medical insurance or the public health system. In New Zealand, if a woman decides to opt for the non-invasive route, she has to carry the full burden of the cost. Currently, this amounts to about $NZ650 (equivalent to £325). In comparison to other centres, this is relatively cheap and elsewhere the test may cost twice as much. Thus, the take-up for testing has been slow. Predictably it has proved popular with the usual suspects, the 'wealthy worried well'. In my experience, laboratory testing/technology will become cheaper with time. It is not unreasonable to expect testing to eventually integrate into the public system without cost to the patient. Presumably this decision will be based on a cost-benefit analysis. If all pregnant women receive ‘free’ non-invasive testing there will be fewer invasive tests and therefore, cost savings, but only if non-invasive testing becomes relatively cheap- watch this space. Obviously I can only comment with regard to the New Zealand experience although most Western nations follow a similar model.

I’d like to finish with a word about the dark implications of genetic testing. What I’m about to say throws more light on society than it sheds on the science and scientists implementing and practising genetics. Some argue that genetic testing, especially as it relates to the prenatal context, evokes the dark image of eugenics and the prospect of ‘designer babies’. In a way, this has already happened. In some societies, there is a bias toward male children and a decision to abort an otherwise healthy baby is made on the basis of sex alone. China is facing a demographic time-bomb due to this wide spread practice. There will come a time when it will be possible to determine a host of genetic features of an unborn baby from a simple maternal blood test. Will some couples abort a pregnancy based on genetic characteristics which have no clinical relevance but impinge on intelligence or aesthetic qualities, especially if testing is performed very early in the pregnancy? Repugnant as this may seem to most, there will always be those who will abuse the power of genetic testing.  Where money is involved, everything becomes possible. Call me a cynical old scrote (call me a cab), but I honestly believe effective regulation of genetic technology to prevent misuse, especially at the prenatal level, is ultimately doomed and futile- a brave new world indeed.

I want the tall, blond haired, blue eyed one, of course


  1. Well, you may end up with a pretty child, but it will probably not be quite what you expected. Could be mad as a hatter.

    1. Yep, behavioural/pyschological traits are tougher to identify as they tend to be genetically complex. A number of genes interacting with each other and the environment. The more we delve the more intricate and labrynthine the picture becomes.