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13.1 How has the field of pre-natal testing changed, since such techniques were first developed? Consider the sampling and analysis methods available, and our advancing understanding of conditions that may be diagnosed pre-natally.
At first, pre-natal testing was possible only via invasive methods. Amniocentesis was developed experimentally in the late 1800s, and became used routinely in the second half of the twentieth century. Ultrasonic guidance of sampling needles improved the safety of the procedure considerably, but it still carries a risk of pregnancy loss. Sloughed-off foetal cells are extracted from sampled amniotic fluid, and cultured in vitro. Laboratory tests that can be done upon such cells have developed considerably in their range and complexity: at first, only karyotyping was performed, but now a full range of molecular genetic tests, such as Digital PCR and genomic sequencing are possible.
Amniocentesis was, and still is, only effective from the second trimester of pregnancy. There was, therefore, a need for the development of a pre-natal testing technique that was effective at an earlier gestational age. Chorionic villus sampling (CVS) can be performed from the 10th week of pregnancy. It was first developed in the late 1960s, but became adopted widely only in the 1980s, when the introduction of fine-needle aspiration biopsy reduced the associated risk of pregnancy loss to levels considered acceptable. Like amniocentesis, the range of, and level of genetic detail available from, sample interrogation techniques has improved considerably to the present day.
Alongside pre-natal diagnostic tests, the latter part of the twentieth century saw the development of pre-natal screening tests, which are less sensitive and specific than diagnostic techniques, but carry no procedural risk to the foetus. Developed countries therefore instituted nationwide pre-natal screening programmes for common foetal abnormalities, based upon protein markers in maternal serum. Only women whose pregnancies are deemed ‘high risk’ from screening test results are offered subsequent invasive testing. In common use are the Triple Test and Quadruple Test - which measure levels of three and four proteins, respectively - and the Combined Test, which involves both protein level detection and ultrasonography.
Much of the pre-natal testing effort employed, both historically and presently, is aimed at detecting the common aneuploidies: trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome). These can be detected directly, via karyotyping. In a similar vein, detection of the Y chromosome has also featured prominently. For example, early amniocentesis trials were focussed upon pre-natal sex detection in a family where boys had a high chance of inheriting the sex-linked genetic disease, haemophilia. With the introduction of maternal serum protein level markers and ultrasound, developmental abnormalities such as spina bifida became another key target of screening - in addition to analysis of such maternal protein markers to find signature levels associated with the trisomies mentioned above. As PCR-based, CGH-based, and sequencing-based techniques have evolved, the range of diseases that can be pre-natally detected has expanded; disorders caused by a single gene mutation - such as cystic fibrosis - and disorders caused by subtle chromosomal changes - such as Smith–Magenis syndrome – can now be diagnosed pre-natally.
The next step-change in pre-natal testing came from the discovery of foetal genetic material in maternal blood. Although foetal cells had been detected in the maternal circulation as early as the 1960s, it was only with the discovery of foetal cell-free DNA (cffDNA) in maternal plasma, in the late 1990s, that workable non-invasive pre-natal genetic testing techniques could be developed. In addition to the wide array of possible DNA-based tests that can be conducted with cffDNA, the approach carries two further advantages: 1.) cffDNA is detectable in maternal serum from the seventh week of pregnancy; and 2.) cffDNA tests for aneuploidies are so sensitive and specific, it is widely thought that confirmatory invasive testing is not required.
Alongside the scientific and technological developments in the field of pre-natal testing, the area is affected by socio-political choices. In general, the historical trend in developed countries has been toward a greater availability of testing to all pregnant women, at as early a stage in pregnancy as possible. Funding decisions, naturally, play a part in this. At the time of writing, the UK NHS is considering whether to offer cffDNA testing to all pregnant women, at no additional cost – a notion that has raised debate among anti-abortion and pro-choice groups, and disability rights campaigners.
13.2 Some conditions may be diagnosed either pre-natally or neo-natally. Give appropriate examples to illustrate this point, highlighting the testing methods involved. What are the advantages and disadvantages of these approaches?
With the advent of modern pre-natal genetic testing methods, in theory, the genome of every foetus could be sequenced fully, and thus any and all genetic disease conditions and predispositions, revealed before birth. It is not, however, currently cost-effective to do this, and the ethical implications of such a choice, on a national level, would take much debate.
Let us consider, then, the current testing possibilities. Cystic fibrosis can be detected pre-natally from directly-sampled foetal DNA, or from cffDNA in maternal blood; such screening is generally offered only to families in which the parents are known to be carriers, and may be combined with assisted reproduction technologies. An advantage of this approach is that resources are focused on families that need it most, but a disadvantage is that cystic fibrosis may go undetected in other pregnancies. Many developed countries also screen for cystic fibrosis at birth, using an immunoassay to report immunoreactive trypsinogen levels in the newborn’s blood. The aim of such screening is to treat sufferers of the condition as quickly as possible, and thus optimise their prognosis.
Although modern therapies for cystic fibrosis can considerably extend life expectancy and health, they cannot eliminate all symptoms of the disease. This is in contrast to treatments for other neo-natally-screened disorders, for which prompt and lifelong treatment can restore excellent health and normal life expectancy. For example, mass-spectrometry measurements of amino-acid and fatty-acid levels in infant blood can be used to diagnose a range of metabolic diseases, including phenylketonuria and maple syrup urine disease. Also, detection of low levels of thyroid hormones by immunoassay in the neo-natal period can lead directly to hormonal supplementation, thus eliminating the symptoms of congenital hypothyroidism. One could argue that neo-natal screening for such disorders is more appropriate than pre-natal screening, owing to the existence of these effective treatments.
In ethical terms, the advantages and disadvantages of pre-natal and neo-natal testing are very much informed by individual views and beliefs. Although some pre-natal testing is done with a mind to prepare as well as possible for the arrival of a disabled child, it is implicit in many pre-natal testing schemes that a pregnant woman will be offered the option of an abortion, should the test detect an abnormality. Some, who would prefer not to have a child suffering from a genetic condition or developmental disorder, consider this choice an advantage, whereas diagnosis at birth would be considered ‘too late’. Others feel that the purposeful termination of any pregnancy is undesirable.