Biomedicine Workshop – Genetic Tests PRENATAL DIAGNOSIS: SCIENTIFIC/EPIDEMIOLOGICAL ASPECTS AND THE CURRENT SITUATION IN ITALY 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 world. 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 tests). 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 past. 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 regard. 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. 6) - 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 specialisation. 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 women. 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.