Biomedicine Workshop – Genetic Tests

Biomedicine Workshop – Genetic Tests
by Claudio Giorlandino
University lecturer and Scientific Director of the Artemisia Institute, Rome
The study of the state of prenatal diagnosis in Italy took into consideration the most "calculable" and
measurable aspects of the phenomenon which, as we will see, is on the rise throughout the Western
The situation in Italy is reflective of the emerging situation in the rest of the Western world.
In France, where genetic laboratories are very widespread, there are more than half the number of
Italian laboratories in Paris alone (it is estimated that there are more than 200 private and public analysislaboratories in this city, almost all of which offer a wide range of molecular biological and/or cytogenic
In the United States and England, there are so many centres that it is impossible to determine the
exact number. The only assessable data is that relative to DNA tests done in the U.S. as part of forensic
work. In 2000, they amounted to approximately 148,000 (source: Forensic Nurse 2003). If, in the United
States, as in our country, the numerical relationship between clinical genetic tests and forensic genetic
tests is greater than 100:1, this would mean that tens of millions of molecular biological tests are done in
the United States each year.
Moreover, it suffices to consult the industry producing and distributing diagnostic kits in order for
these figures to be confirmed.
Even in Sweden, considered by some to be an example of the proper use of genetic laboratories
(and accepting, for the sake of argument, that Europe and the United States should follow the example of
a country with a social/health system with which the Italian, English, German, French and North American
systems cannot compare), private medicine has been on the rise for a number of years. It suffices to leaf
through the Gula Sidorna (the Swedish Yellow Pages) to find numerous private DNA-analysis centres.
To be honest, every reference to the possibility of following the Swedish model is cause for a smile. In
Sweden, where the health care is almost entirely provided by the state, doctors work exclusively
according to national cost-benefit guidelines (in order to optimise consumption). One need only consider
that, in Sweden, the relatives of a surgery patient may stay, at no cost to them, in a “patient hotel" for the
entire duration of an operation.
Prenatal diagnosis is steadily increasing around the world. The most recent annual report of the
International Clearinghouse for Birth Defects Monitoring System states that the percentage of women
under the age of 34 years requesting amniocentesis has risen in all countries (and not only in Italy), from
20% in 1993 to 50% in 1999 and continues to rise.
As far as pre-implantation genetic tests are concerned, even though the World Health
Organisation (2002 Publications and Documents of the Department of Reproductive Health and
Research, Family and Community Health, Geneva) emphasises the great importance and necessity of
such tests, the law in force on fertilisation (currently being repealed by an abrogative referendum)
prohibits them.
In order to dispel any doubt regarding the mismanagement of genetics in Italy, it is only fair to
consider the following:
the number of genetic centres is progressively increasing throughout the Western world,
increasing by the thousands as a consequence of the extraordinary interest manifest by both
scientists and the public at large. According to data on invasive prenatal diagnosis presented
at the recent Los Angeles symposium of the American Society of Human Genetics, 1 woman
in 4 (25%) in the United States has amniocentesis performed. In France, 60% of the women
who undergo prenatal diagnosis do so in the private sector because they are under the
National Health Service's age limit. In the United Kingdom, prenatal screening programs are
being launched that will include not only cytogenetic diagnosis but also tests for cystic fibrosis
and fragile X.
performing invasive prenatal tests only on women above the age of 35 (in the '70s, it was
estimated that the risk of having a Downs child was greater than the risk of miscarriage
implicit to the procedure) is no longer a valid consideration and is no longer accepted for the
following reasons.
1) The risk of miscarriage as a result of amniocentesis is now much lower than in the
2) The negative experience of having a child with a chromosomal anomaly is the same at
20 years of age as at 40 years of age and, even if the risk is lower in younger women,
couples today want few but healthy children. Moreover, it is almost exclusively young
women who give birth to children with karyotype anomalies (older women undergo
prenatal diagnosis).
2) The number of these tests done is increasing exponentially around the world (see the
annual report of the International Clearinghouse for Birth Defects Monitoring
Systems). According to the international data reported, Italy is on a par (and not
ahead of) other countries (such as France, England and the United States) in this
3) Other data from the annual report of the International Clearinghouse for Birth Defects
Monitoring Systems show that, in countries such as Italy where prenatal diagnosis is
on the rise, the number of births with anomalies is decreasing. The differences are
dramatic in countries, such as Norway, where there are fewer prenatal diagnoses. In
Norway, 12 out of 1000 foetuses are born with Downs; in Italy, there are fewer than 3
per 1000;
4) Current DNA tests screen for many genetic diseases, giving parents peace of mind.
These tests are about to become even more reliable and, with the introduction of
nanotechnologies and diagnostic microchips, increasingly free of error and
increasingly more complete.
5) The law rules that maternity must be free and responsible. A family, if it so wishes,
therefore has the absolute right to be informed about the state of health of a child
before it is born. All the more so because such tests, when done for young couples,
are not a cost burden to the NHS, since it does not cover such tests.
Medical/legal disputes arise EXCLUSIVELY out of cases in which diagnosis has not
been made (irrespective of age). No complaint has ever been made about too many
tests having been done.
Each individual's free choice to submit to, and pay for, a diagnostic test is still, in our country,
fortunately, guaranteed and protected by the law and by the Constitution.
But, above all:
Western medicine is at a turning point: no longer disease medicine, it is becoming preventive
medicine, and this is only possible through genetic tests (diagnostic and susceptibility tests).
The merit of genetic tests, above and beyond prevention, is due to health-care savings. Let
us consider the consequences of a negative genetic test. One thinks of how much is saved
because less routine tests and check-ups are done. One thinks of the enormous reduction in
the consumption of preventive medicines and, above all, of the invaluable peace of mind
given to so many people terrified, for example, by the presence of a specific familiarity, who
are then reassured by a DNA test.
All specialists, cardiologists, obstetricians, paediatricians, oncologists, etc., have available to
them a diagnostic and predictive arsenal that was once unthinkable and is now widely
available and about to become even more available. Increasingly, physicians will rely less on
intuition and the laws of probability governing genetic randomness and more on simple,
inexpensive, certain tests.
But, when the situation here in Italy is examined in greater detail, as requested by the current Minister of
Equal Opportunity, Stefania Prestigiacomo (who set up an ad hoc commission for this purpose), the
following becomes evident.
In the Trentino Alto Adige area, recourse to invasive prenatal diagnosis is rather high, due to the
progressive rise in the age of pregnant women (14% above the age of 34 years). Although the available
data are not certain, due to obvious and serious underreporting, it is possible to estimate that, in the
population at greatest risk (above the age of 34 years), recourse to invasive prenatal diagnosis does not
exceed 50%.
Much clearer is the obvious and profound difference between the cities and the valleys and the
difference among ethnic groups, defined on the basis of ideological and, particularly, cultural identifiers.
There are a number of curious differences among the ethnic groups, such as requests to know
the sex of the unborn child, which is more frequent in the Italian-speaking population and rarer in the
German- and Ladin-speaking population.
In the Triveneto area, demand is on the rise. The law states that 3 ultrasound scans may be
done, at no cost to the patient, for each pregnancy. In spite of the increase in the number of public
ultrasound centres, many pregnant women are unable to have scans performed at regional or
conventional centres and turn to private facilities.
The quality of the tests, whether done at private or public centres, is considered good in
approximately 60% of cases. User satisfaction is at the same level. There is a lack of co-ordination of
the procedures which pregnant women must follow if in-depth tests must be done or if problems arise.
Given the great many facilities that offer invasive prenatal diagnosis, many of them only perform a
limited number of these tests. This results in lower service quality and increased expenses. In fact, more
than 80% of the hospitals in the Triveneto area perform amniocentesis and approximately 60% perform
chorioxic villus sampling (CVS).
There is no precise data on access to invasive prenatal diagnosis. It is known, on the other hand,
that there is a progressive increase in requests for amniocentesis (13%) and CVS (10%), without there
being any specific need for the tests.
The number of cytogenic laboratories, both private and public, is insufficient to meet demand with
the result that women travel to other Regions for this service.
In the Friuli-Venice-Giulia area as well, the number of women over the age of 35 years who give birth has
increased in the last decade, from 12% to 20%. Recourse to invasive prenatal diagnosis has
consequently also increased. At the present time, it is performed for 20% of pregnancies in this Region.
More than 90% of demand is covered by the area's 10 prenatal diagnosis centres.
It should be pointed out that, depending on the operators' cultural orientation, there is a
progressive increase in screening tests, particularly nuchal translucence.
In Piedmont, 34,000 babies are born each year. The percentage of women giving birth around
the age of 35 years has increased to 19%. Hospital facilities and operators dealing with prenatal
medicine are increasing progressively. Screening is based largely on the Tritest which, as opposed to the
case in other Regions, remains the traditional practice (largely due to the fact that this method was first
developed in Turin, 20 years ago).
There are relatively few invasive prenatal diagnoses. Approximately 5500 amniocenteses and
approximately 500 CVS at public facilities and 300 prenatal diagnoses in private clinics. These figures
correspond to only 4% of women who give birth. Even if this percentage is considerably underestimated,
it must be considered that recourse to invasive prenatal diagnosis is low in this Region.
Almost all services are public. There are very few private, accredited clinics. The service in the
hospitals is good. Most of the prenatal tests are done at the Sant’Anna Hospital, which handles
approximately 1/5 of the births in Piedmont. The service is very well run and it would seem that the level
of user satisfaction is high.
There are many small, underused walk-in clinics in the area; on the other hand, the larger or
reference facilities sometimes lack the necessary equipment.
The Valle d’Aosta may be considered as something of an ideal laboratory for study of the
dynamics in this field, given that there is only one hospital with only one obstetrics/gynaecology
department and hence only one birth centre for the entire Region. There are no private clinics. There is
high demand for prenatal diagnosis (amniocentesis), which is performed on 50% of the pregnant women
in the area.
Given the regional epidemiology, there is little experience with management of rare pathologies.
There is a need for highly specialised centres with large caseloads able to deal with the problems
inherent to prenatal diagnosis.
In the Region of Liguria, there are 12 hospital centres performing prenatal diagnosis. No data is
available on private clinics. Approximately 11,000 babies are born in the Region each year.
On the basis of Law 3 of 19 January 2001 and of Executive Council Directive no. 1562 of 20
December 2001, a Department of Genetics was set up for the Region. It combined all of the genetic
services established in previous years, including all of the university clinics, scientific institutes, hospitals
and individual researchers, which together had made this Region a point of reference for a range of
genetically transmitted diseases. At the present time, the department operates 4 high-level genetics
facilities and 15 genetics/molecular biology laboratories in various integrated facilities. In 2001,
approximately 3700 invasive prenatal diagnoses were performed. Of these, approximately 3100 were
done in public facilities and approximately 600 in private clinics. There are 5 laboratories (3 public and 2
private) 13 sampling centres and 35 operators.
According to information provided by the Genetics Society (unconfirmed data), services should
have a catchment area of not less than 2.5-3 million inhabitants (minimal European parameters) in order
to fulfil the criteria governing efficiency, quality and low cost.
Within this context, the Ligurian system would seem to be exaggeratedly large given regional
requirements. It should be pointed out, however, that a very large number of prenatal diagnoses are
done for patients from other Regions. In any case, the network of genetic-diagnosis services is
undoubtedly oversized and disproportionate with respect to European standards (according to data again, unconfirmed - from the Human Genetics Society, 36% of molecular-genetics services in Europe
are located in Italy).
In Emilia Romagna, a survey done in 1997 shows that each pregnant woman has at least 5
ultrasound scans done and that 20% of pregnant women undergo invasive prenatal diagnosis.
The outcome of prenatal diagnosis is demonstrated by a reduction in the number of congenital
deformations at birth, particularly Down's syndrome.
There is disproportionate recourse to prenatal diagnosis, exceeding the limits recommended by
scientific bodies, in certain parts of the Region. The resources are often not rationalised and would, if
better used, make it possible to maintain diagnostic efficiency at par while achieving significant savings
on invasive diagnoses.
Prenatal diagnosis and foetal medicine are undergoing very rapid growth. It should be possible to
develop an effective program according to levels of competence. A first level would filter out patients with
pathologies or risk factors; a second and higher level, with more specialised competence, would carry out
diagnosis and therapy, which could require intense, specific intervention (foetal therapies, newborn
surgery, etc.). At the present time, the Region of Emilia Romagna has no such organised system. There
are highly competent centres that function as points of reference without there being any pre-established
procedures for patients. On the other hand, the reference centres are undersized, particularly as far as
obstetrics is concerned. In general, patients for whom prenatal tests reveal pathologies or doubts have
great difficulty in accessing specialised centres.
In the Region of Tuscany, there are 5 major birth centres. There are 10-15 prenatal diagnosis
centres (private and public). 95% of women are correctly informed about invasive prenatal diagnosis. Of
these, 40-50% undergo the procedure. The average age of women who give birth to their first children is
36 years and the Region guarantees them 3 ultrasound scans per pregnancy, free of charge. Apart from
local situations, there is constant, continual improvement of the prenatal diagnostic services provided to
safeguard pregnant women. The Tuscan Registry of Congenital Defects provides a very good picture of
our diagnostic abilities. In its most recent report (2000), it indicated that there is a growing trend to
perform ultrasound examination, comparable and sometimes superior to that documented by other
European registries. Substantially inferior, however, to what is evidenced by registries in the Northeast.
If, on the other hand, we consider the data provided by the Ministry of Health's Integrated Information
System for Congenital Malformations, the Region falls within the average national values.
Prenatal diagnosis (3 ultrasound scans), genetic counselling, invasive diagnosis when performed
and level-II ultrasound scanning cover regional requirements with an acceptable level of satisfaction.
The Region of Tuscany is attentive to the needs of its women. It continually offers refresher
courses for its operators in both the medical and paramedical fields. It is also planning to set up a genetic
counselling clinic.
The prenatal diagnosis offer in the Marche Region is very diversified, extensive and distributed
throughout the area. During 2001, approximately 20% of the pregnant population had screening and
prenatal diagnosis performed. Less than 10% of the pregnant population avails itself of invasive prenatal
diagnosis. Given that the cytogenetics laboratory is essentially totally centralised, this Region’s resources
and laboratory service are rationalised. Nevertheless, it should be pointed out that of the approximately
1000 prenatal diagnoses performed in approximately 10 centres, 7 of these centres perform less than 100
diagnoses annually. This obviously reduces quality to the advantage of distribution throughout the area.
Molise is a small, poor Region. The average cultural level is not high. There are 5 birth centres
(2 I-level, 2 II-level and 1 III-level). The III-level centre has many weak points. The Tritest has not been
successful. Here, as elsewhere, it has increased rather than reduced the number of prenatal diagnoses,
often leading to unjustified anxiety (many false positives).
The prenatal diagnosis centres also deal with pregnancies in which drug dependency and HIV
are involved. The III-level centre is relatively well-organised and user response is good.
There is a lack of economic support and assistance in difficult situations.
In Abruzzo, there are approximately 12,000 births per year. For many of the related services, the
Region's inhabitants make use of facilities in nearby Rome.
Prenatal diagnosis is performed in two centres (Chieti and Pescara), primarily amniocentesis
(approximately 1000 per year), for approximately 8% of pregnancies. Both of these centres operate
within the National Health Service.
There are, however, an undefined number of pregnant women who are not part of these data
because they have prenatal diagnoses performed at private clinics outside the Region. As far as noninvasive diagnosis is concerned, the Chieti and Pescara hospital centres perform approximately 8500
tests per year. The demand for screening is still low. Morphological ultrasound diagnosis is the main
procedure done.
In the Region of Campania, the demand for invasive and non-invasive prenatal diagnosis is
growing rapidly, although accurate epidemiological data are not available. The service offer, from both
public and private centres, is not appropriate to needs in terms of quality. There are 2 III-level public
centres in Naples and a large number of private clinics (operating both within and outside the National
Health Service) throughout the entire Region. However, the lack of regulations has resulted in duplication
and fragmentation of testing, particularly amniocentesis, biochemical screening and prenatal ultrasound
scanning, with a correspondingly excessive number of false positives and superfluous tests. This is the
result of the fact that national standards have been disregarded (see the decree on pregnancy tests),
which expressly identify Regional Reference Centres where diagnostic methods and prenatal screening
are centralised, as occurs in other Regions. However, at least as far as the more complicated prenatal
diagnoses (more or less common or rare genetic diseases) and the management of foetal malformations
are concerned, the II Polyclinic centre offers good services, although it is unable to satisfy all of the
Region's needs.
In Basilicata, there are 11 birth centres but only 5000 births per year. This fragmentation has
resulted in a low level of assistance, especially in the clinical/diagnostic areas, which require high
Invasive prenatal diagnosis - almost exclusively amniocentesis - is performed in 5 centres (4
public and 1 private). The centres are used by approximately 10% of the population.
As is the case in many other Regions, Apulia has many small hospitals, often less than 5 km
apart. It has been pointed out more than once that the health-care system does not meet the objectivity
and logistics criteria necessary for use optimisation and rationalisation. Often, the services offered reflect
other demands, connected to various kinds of interest.
Only 45 of the 66 birth centres provided data. Of these, 15 centres handle less than 500 births
annually; there are other centres handling less than 200 births.
Given the increase in demand for prenatal diagnosis, there are now 15 cytogenetics centres, of
which 10 are public and 5 are private. Genetic counselling is provided in only 8 of these centres.
In 2001, approximately 6000 CVS and amniocenteses were performed. According to experts, the
Region's centres sufficiently cover demand. The University of Bari and the Casa Sollievo della
Sofferenza di San Giovanni Rotondo have excellent medical genetics departments.
As far as ultrasound diagnosis is concerned, the situation appears to be rather chaotic. All of the
region's gynaecological and obstetrics units have, or claim to have, ultrasound-scanning services and are
able to carry out simple, routine tests. Approximately 1/3 of the centres has the proper equipment,
although not necessarily latest-generation.
In the Region of Calabria, requests from couples for prenatal diagnosis are increasing constantly,
due largely to the media, to increased desire for a "healthy" baby, to the fall in the birth-rate and to the
increase in the age of women who conceive. More than 95% of the pregnant population is cared for by
specialists at public clinics (hospitals, walk-in clinics throughout the region, consultants, etc.) and private
clinics. This has meant that pregnant women are cared for with almost full respect for the protocols
covering the monitoring of pregnancy. The increase in immigration to the Region is not to be
underestimated. There is a significant number of women living in the Region, legally or otherwise, whose
social status and lifestyles undoubtedly do not conform to the standards set for the care of pregnant
According to available data, regional genetic centres in the Catanzaro and Reggio Calabria
provincial hospitals satisfy approximately 90% of demand within the Region. Approximately 3500
invasive diagnoses are performed annually (primarily amniocentesis). Most of the Region's hospitals take
amniotic-fluid samples on their own premises and then send them to one of the above-mentioned
laboratories. The number of pregnant women who have invasive prenatal diagnosis done varies between
15 and 20%.
As far as Sicily is concerned, there is a marked difference between the private and public sectors.
The former offers highly specialised, recognised centres (in Palermo and Catania), with excellent
professionals and avant-garde competencies; the level of public-sector organisation throughout the
Region is qualitatively and quantitatively inadequate. There are in fact only 2 official, public centres for
prenatal diagnosis and not even these centres perform all invasive and diagnostic procedures. They
carry out only a few molecular genetic tests. As opposed to the other Regions, where there is a marked
surplus of medical geneticists, at least for I-level genetic counselling, Sicily has a severe lack of
professionals in this field.
The public and private prenatal diagnosis centres do not operate in harmony with the various,
multi-specialised facilities within this field because the latter are scattered throughout the Region.
In Sardinia, the average birth-giving age is 32 years for the first birth and 35 years and up for the
second birth. Given the incidence of chromosopathies in these age ranges, and according to
recommendations made by the WHO and by the Ministerial Decree of 10 September 1998, the National
Health Service in Sardinia should be able to offer approximately 2000-2500 prenatal diagnoses for
determination of foetal karyotype by means of CVS or amniocentesis, after genetic counselling
(informative and non-directive).
The high incidence of healthy carriers of beta-thalassaemia (13% of the Sardinian population)
made it necessary to set up a reference centre (at the Regional Hospital for Microcythemia) that performs
more than 1500 invasive diagnoses/year (early CVS and amniocentesis). A further 1000 amniocenteses
are performed throughout the rest of Sardinia.
The active offer of tests to the population has made it possible to reduce by 30% the requests for
invasive prenatal diagnosis for women above the age of 35 years. During non-directive genetic
counselling, women at risk (over 35) can now be properly informed about the availability of invasive
prenatal diagnosis.
Finally, as far as the Regions of Lazio and Lombardy are concerned, the following differences can
be pointed out. In the Region of Lombardy, a high percentage of women (more than those who turn to
the private sector) make use of the National Health Service for invasive prenatal diagnosis. The actual
percentage of pregnant women who use these services is not easy to deduce because of the large
number of facilities, both private and public, operating throughout the entire Region. According to a
reliable estimate, based on a sample survey and on a report by the Institute of Health, the percentage of
pregnant women who avail themselves of these procedures is around 15-20%.
The situation is different in the Region of Lazio, where prenatal diagnosis is done primarily in
private clinics (not accredited with the NHS) and where the percentage of women who have such
procedures performed would seem to be greater than 35%.
In conclusion, we can say that the desire to know the unborn child’s state of health is widespread
and, with obvious regional differences, that this interest is growing progressively throughout the country.