10th EUROCAT European Symposium
Bilbao, Spain, 10 June 2009
Main Lecture
Health Surveillance and Rare Diseases Action: Europe's Challenges [Presentation]
Risk Factors in Congenital Anomalies and Prevention
Environmental Risk Factors of Congenital Anomalies [Presentation]
Drugs and Pregnancy [Presentation]
Folic Acid and the Prevention of Neural Tube Defects: What Have We Achieved in 18 Years? [Presentation]
Maternal Obesity and Congenital Anomaly Risk: A Growing Problem [Presentation]
Prenatal Diagnosis and Genetic Counselling
An Overview on Antenatal Screening for Down's Syndrome [Presentation]
Assisted Reproduction Techniques: A Small Risk for the Newborn but a Great Prevention of a Number of
Conditions [Presentation]
Genetic Counselling in Health Care: Present and Future [Presentation]
Quality Assurance in Genetic Testing: A European Perspective [Presentation]
Ethical and Legal Issues on Prenatal Diagnosis and Genetic Counselling in Europe
Selected Oral Communications
Radiological Techniques in the Fetal Autopsy with Suspicion of Prenatal Malformations [Presentation]
Birth Cohort Studies in Europe [Presentation]
International Trends of Down Syndrome, 1993-2004 [Presentation]
Congenital Heart Defects [Presentation]
Predictors of Survival for Birth to 15 Years for Children with Congenital Heart Defects [Presentation]
Impact of Assisted Reproductive Technologies on the Risk of Neural Tube Defects: A Registry-Based Evaluation
[Presentation]
Genetic Counselling in Congenital Anomalies in the Basque Country and Recommendations for Improving its
Provision [Presentation]
European Commission's Perspective on Developing Health Surveillance and Rare Diseases Action
A Montserrat
Rare diseases, including those of genetic origin, are life-threatening or chronically debilitating diseases which are of such low prevalence (less than 5 per 10,000) that special combined efforts are needed to address them so as to prevent significant morbidity or perinatal or early mortality or a considerable reduction in an individual's quality of life or socio-economic potential. It is estimated that between 5,000 and 8,000 distinct rare diseases exist today, afeting between 6% and 8% of the population in total. In other words, between 27 and 36 million people in the European Union (with 27 Member States) are affected by a rare disease. The specificities of rare diseases - limited number of patients and scarcity of relevant knowledge and expertise - single them out as a unique domain of very high European added-value. There is probably no other area in health where the collaboration between the 27 different national approaches can be as efficient and effective as rare diseases. The need to pool together the very limited resources could be better addresses in a co-ordinated way at EU level.
The objective of the European Union action in the field of rare diseases is to put together the necessary elements for an efficient overall strategy addressing the important issue of Rare Diseases in Europe. The strategic objective of the EC intervention in this field is aimed at improving the chance for patients to get appropriate and timely diagnosis, information and care through European action that can act more effectively than the Member States on their own. This requires:
- making rare diseases more visible through developing proper identification and coding of rare diseases, many of
which currently go unrecognised leading to inappropriate treatment for individuals and lack of appropriate resources
overall;
- encouraging EU - 27 in developing national plans for rare diseases in their health policies to ensure equal access
and availability of prevention, diagnosis, treatment and rehabilitation for people with rare diseases. More initiatives
in terms of public awareness-raising in the MS are needed. In addition to targeting public opinion, these efforts
should also be directed at professionals in healthcare and social services, decision-makers, managers of health
and social services and media.
- providing European support and co-operation, such as ensuring that common policy guidelines are developed and
shared everywhere in Europe; specific actions - in areas such as research, centres of expertise, access to
information, incentives for the development of orphan drugs and screening. Co-operation between exisitng
European programmes focused around this issue also needs to be improved.
Based in Article 152, a Community action programme on rare diseases including genetic diseases, was adopted for the period 1 January 1999 to 31 December 2003. Rare diseases were also one of the priorities in the EU Public Health Programme 2003-2007. Decision 1350/2007/EC of the European Parliament and of the Council adopting the second programme of Community action in the field of health (2008-2013) establishes in point 2.2.2 of the Annex: "Promote action on the prevention of major diseases of particular significance in view of the overall burden of diseases in the Community, and on rare diseases, where Community action by tackling their determinants can provide significant added valude to national efforts". The White Paper COM(2007) 630 final "Together for Health: A Strategic Approach for the EU 2008-2013" of 23 October 2007 developing the EU Health Strategy also identified rare diseases as a priority for action. A substantial contribution to advancing knowledge on rare diseases has been provided for two decades through collaborative and co-ordination research projects supported by the successive European Community Framework Programmes for Research and Technological Development. In the current framework programme, FP7, rare diseases have been recognised a priority for research activities.
An excellent example of the type of projects that the European Union can support in the field of rare diseases is EUROCAT (Surveillance of Congenital Anomalies in Europe). EUROCAT provides essential epidemiological information on congenital anomalies in Europe based on a common dataset with common coding as specified in the EUROCAT Guide and the EUROCAT Data Management Programme (EDMP) used by member registries for data input/import, validation and annual transmission of the Central Registry. They act as an information and resource centre for the population, health professionals and managers regarding clusters or exposures or risk factors of concern. They provide a ready collaborative network and infrastructure for research into the causes and prevention of congenital anomalies and the treatment and care of affected children, and survey policies and practices with regard to periconceptional folic acid supplementation.
Under normal market conditions, the pharmaceutical industry is reluctant to invest into medicinal products and medical devices for rare conditions because of the very limited market for each disease. Under the responsibility of DG ENTR and the EMEA (the European Medicines Agency) the EC implements a policy on Orphan Drugs. The Orphan Medicinal Product Regulation (Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products) was proposed to set up the criteria for orphan designation in the EU and describes the incentives (eg. 10 year market exclusivity, protocol assistance, access to the Centralised Procedure for Marketing Authorisation) to encourage the research, development and marking of medicines to treat, prevent or diagnose RD.
DG Sanco has established the High Level Group on Health Services and Medical Care (HLG) as a means of taking forward the recommendations made by the reflection process on patient mobility. One of the Working Groups of this High Level Group deals with reference networks of centers of expertise, in particular for rare diseases.
The Commission has adopted the Commission Communication COM(2008) 679 on a European action in the field of rare diseases and a draft for Council recommendation (to be approved on 9 June 2009 under Czech Presidency of the Council). Both initiatives aim to improve the chance for patients to get appropriate care and information on rare diseases and to reverse the current situation of uncertainty and invisibility for people suffering from a rare disease. Health professionals and public health authorities have insufficient knowledge of the majority of rare diseases. This lack of knowledge underlies diagnostic error - a great source of suffering for patients and their families - and delayed care provision, which can sometimes be prejudicial. Proposals are still being developed, but are currently structured around ten specific objectives and actions:
1. To improve information, identification and knowledge on rare diseases.
2. To improve prevention, diagnosis and care of patients with rare diseases.
3. To develop national/regional centres of reference and establish EU reference networks.
4. To help ensure equal access to all EU patients to orphan drugs and compassionate use.
5. To help to develop specialised and adapted social services for rare diseases patients.
6. To accelerate research and developments in the field of rare diseases and orphan drugs in order to strengthen
at European level the limited and scattered expertise on rare diseases.
7. To empower patients with rare diseases at individual and collective level.
8. To support implementation on National Plans for rare diseases.
9. To develop international co-operation on rare diseases.
10.To co-ordinate relevant policies and initiatives at EU level.
The Commission Communication and the proposal for a Council Recommendation will require intensive work on implementation involving (eg. creation of the EU Committee of Experts on Rare Disease, launching a European Research Foundation on Rare Diseases, codification of more than 2,000 rare diseases in the next International Classification of Disease, report on the bottlenecks in the existing system of orphan drugs, EU guidelines on compassionate use, EU guidelines for the European reference Networks for rare diseases etc).
Environmental Risk Factors and Congenital Anomalies
M Nieuwenhuijsen
In this paper we will review the current literature on environmental risk factors of congenital anomalies. The focus will be on frequently occurring environmental pollutants or contaminants in our everyday environment such as water contaminants like chlorination by-products, traffic related air pollutants, exposure to waste disposal products and bystander pesticides.
There is a growing body of epidemiological studies investigating the associations, if any, between chlorination by-products, traffic related air pollutants, exposure to waste disposal products and bystander pesticides and congenital anomalies but the findings have generally been inconsistent and inconclusive.
Epidemiological studies examining environmental risk factors are generally difficult to conduct because of issues related to, for example, case ascertainment, exposure assessment, bias, confounding, small risks, and power. The number of cases and the expected risks are generally small and the exposure assessment crude which makes it particularly difficult. However there are a number of improvements in exposure assessment which may aid the conduct of studies and these will be the focus of the presentation.
Risk Associated with Selective Serotnin Reuptake Inhibitors in Pregnancy: Prospective and Retrospective Studies
E Rodriguez-Pinilla
During the last decade a large number of studies have been published about the potential teratogenicity of selective serotonin reuptake inhibitors (SSRIs), using different study designs and methodologies. However, despite this large number of publications, a clear consensus about the teratogenicity of these antidepressant drugs has not been achieved yet. This situation creates a great concern, especially when we face a women asking for risk assessment.
Several questions have not been completely solved about the potential teratogenicity of SSRI: Can we consider a "class effect"?, Can we consider that significant differences exist between some SSRI and others?, Should we inform the depressive pregnant women on treatment with SSRI about a teratogenic risk?, or is this information only useful for physicians (in order to make a prenatal diagnosis)? Regarding this, we must not forget that these drugs are prescribed to control diseases such as depression, thus we should be very cautious with the information given to this type of patient, due to the harmful consequences to which this can lead.
Thus answers to the previous questions are not easy, even more in the age of the computer, in which everyone has access to information via internet and not informing a patient could be criminally punished.
The current confusion maybe due, at least in part, to difficulties in conducting surveys on clinical teratology on rare diseases and exposures of low use in the population. Moreover, if we keep in mind that congenital malformations individually have a very low prevalence and, thus, it is very difficult to detect associations depending on the study design.
To check if different methodologies can produce different results, we studied associations between maternal use of SSRIs during pregnancy and the risk of birth defects using a retrospective study based on data from the Spanish Collaborative Study of Congenital Malformations (EDEMC), an ongoing, hospital-based, case-control study of environmental and genetic risk factors for major and/or minor congenital anomalies, and a prospective study based on data from the SITTE (Spanish Teratology Information Service).
Our retrospective study suggests a very low increase in the global risk for congenital defects associated with the use of SSRIs during the first trimester and confirms a stronger teratogenic effect of paroxetine, particularly at the CNS level. On the other hand, the results of the prospective study support previously reported risk for ventricular haemorrhage and other neonatal complications, but does not find a significant relationship with major congenital defects.
Folic Acid and the Prevention of Neural Tube Defects: What Have We Achieved in 18 Years?
Bower C
In 1983, Professor Mark J Elwood stated that "if it is confirmed that a reduction of over 80% in the risk of these severe congenital defects [neural tube defects] can be produced by a widely available and inexpensive nutritional supplement, this is one of the great medical advances of the century". The publication of two major randomised controlled trials in 1991 and 1992 confirmed just that - periconceptional folic acid supplementation prevented 70-100% of neural tube defects (NTD).
So, what have we done with this "great medical advance" since the early 1990s?
Many countries have published recommendations that women of childbearing age (or women planning a pregnancy) should take a periconceptional folic acid supplement for at leat one month before becoming pregnant and for the first three months of pregnancy and some have also recommended an increase in dietary folate intake periconceptionally. The public health message is deceptively simple - periconceptional folic acid supplementation prevents neural tube defects, but a major hurdle is the need for adequate folate very early in pregnancy - the neural tube is closed by the end of the sixth week after a woman's last menstrual period.
No jurisdication has been able to achieve better than 50% of women taking the recommended dose of folic acid supplement periconceptionally, in many it is much less than 50% and has not even been estimated in others, and there is only limited evaluation of the effectiveness of public health promotion of supplement use in preventing NTD.
Many pregnancies are unplanned, promotion of folic acid supplements must occur continually to reach each cohort of women entering their childbearing years, and women who take supplements tend to be of higher socio-economic status. These factors may explain the low propoprtion of women taking folic acid supplements periconceptionally and, because of this, a passive rather than an active means of increasing folate intake, such as mandatory fortification of food, has been considered by many countries as a way fo reaching most of the target population and in a more equitable manner.
Several studies have been undertaken to evaluate the effect of fortification and have shown a reduction in NTD ranging from around 20% to greater than 50% reduction compared with the pre-fortification era.
Evaluation of the effectiveness of these measures has been undertaken largely by research groups and, usually, on an ad hoc basis. Monitoring of such public health interventions should be the responsibility of state and national health authorities, but there is little evidence of an a priori, coherent and on-going plan having been established in any jurisdiction.
An ideal system would be independent, well-resourced and matained. It should monitor NTD (and this must include terminations of pregnancy as well as births), fortification, supplement use and folate status of the population (not just women of child-bearing age), and other possible beneficial effects of folate such as prevention of anaemia and other birth defects. Importantly, it should also monitor potential adverse effects of folic acid, in particularly the recent concerns about the effect of folic acid in increasing some cancers.
In 18 years, we have seen a modest increase in the use of folic acid supplements periconceptionally, some countries have fortified a staple food with folic acid, and there has been a reported reduction in NTD, particularly in places where fortification with folic acid has been introduced. However, there are many parts of the world where there has been little or no promotion of supplement use and no fortification and hence, many children have been born with NTD and many pregnancies terminated with NTD since this "great medical advance" was first confirmed.
Maternal Obesity and Congenital Anomalies Risk: A Growing Concern
Rankin J
Obesity is a major public health and economic problem of global significance. The US Surgeon General has called for action on obesity with particular focus on risks associated with pregnancy. Within the UK, the Confidential Enquiry into Maternal and Child Deaths report concluded that maternal obesity (defined as a body mass index (BMI) ≥30Kg/m2) is associated with a higher risk of maternal morbidity and mortality, especially among women from lower social classes who are most at risk of obesity. The prevalence of obesity among women of childbearing age (16-44 years) in the UK is increasing, from 36% in 1993 to 53% in 2003. Regional variations in the prevalence of obesity have been demonstrated, with the North East of England having the highest regional prevalence.
A number of adverse health outcomes of maternal obesity, for both the mother and infant, have been reported. Health implications for the mother include increased risk of: insulin resistance and gestational diabetes, hypertensive disorders, thromboembolic disorders, increased blood loss during labour, haemorrhage, increased caesarean section rates and wound infection. For the infant, maternal obesity is associated with increased birthweight, stillbirth and neonatal death, fetal macrosomia, infant birth trauma and shoulder dystocia during delivery.
There is an accumulating body of evidence suggesting that maternal obesity is associated with an increased risk of congenital anomlies. Studies mainly from the US have suggested an association between maternal obesity and neural tube defects, and cardiac anomalies. Although maternal obesity has been associated with other congenital anomly subtypes, the evidence for these links is less consistent. Maternal underweight has also been linked with the occurrence of specific congenital anomalies, for example gastroschisis. A gradient in response has been reported, with increasing maternal BMA being associated with an increase in risk. However, there are a number of limitations to these existing studies: sample sizes have been too small to evaluate individual congenital anomaly subtypes which may have different aetiologies; not all studies included cases of congenital anomalies occurring in terminations of pregnancy or late miscarriages; the validity of the diagnosis of some congenital anomalies was acknowledged to be low; studies have been case control in design with low response rates; and studies have relied on self-reported weight and height rather than using standardised measures. The lack of consistency on the definition of obesity used also makes comparison between studies difficult.
There are currently no UK studies of the association between maternal obesity and congenital anomlies. The aim of this presentation is two-fold. (1) to present data from a recently completed systematic review and meta-analysis which assessed the current evidence relating to the association between maternal overweight, maternal obesity and congenital anomly risk: and (2) to present data from a retrospective cohort study of pregnant women who booked in one of five hospitals in the Northern Region (UK) and data from the Northern Congenital Abnormality Survey to investigate the relationship beween maternal obesity at booking and the prevalence of congenital anomalies.
An Overview on Antenatal Screening for Down's Syndrome
Boyd P and Wellesley D
The criteria for any screening programme are that the disorder screened for should be clinically well defined; the prevalence known; the disorder associated with significant morbidity or mortality; effective treatment should be available; there should be a period before onset of the disorder during which intervention is possible to improve outcome or allow informed choice; the screening test should be ethical, safe, simple and robust and accessible to all who may benefit from it; screening should be cost-effective (www.ncchta.org/project/908.asp). How many of these criteria apply to antenatal Down's Syndrome screening programmes and the balance between whether they result in overall harm (eg. increased anxiety, further tests in healthy people, false negative cases) or good (eg. reduction in mortality or morbidity) remains debatable.
Down's syndrome was shown to be associated with maternal age more than 75 years ago. It is 50 years since the presence of the extra chromosome 21 was identified and 40 years since the first prenatal diagnosis was made. Screening programmes for Down's syndrome, by identifying pregnant women at higher risk and offering them a diagnostic test, started initially by selecting older mothers and offering them an amniocentesis test. Such a programme, by offering around 5% of women (usually women aged over 35-37 years) an amniocentesis, detected about 30% of pregnancies with Down's syndrome. Most parents with a prenatal diangosis of Down's syndrome opt for termination of pregnancy (www.wolfson.qmul.ac.uk/ndscr).
Since 1987, when, in addition to screening by maternal age a biochemical screening test was intriduced, numerous new tests have evolved, each with different detection and screen positive rates. The first biochemical marker identified, a low level of alpha-feto-protein (AFP) led, after evaluation, to the double test - screening on the basis of information on maternal age and serum AFP. This, offered in the second trimester, identified about 35% of Down's syndrome pregnancies for a 5% screen positive rate, an improvement of 5% on maternal age alone. Shortly after this, maternal serum human chorionic gonedotrophin (hCG) levels were shown to be high in affected pregnancies and maternal serum unconjungated oestriol (uE3) low. These two markers, with AFP and maternal age formed the basis of the second trimester Triple test which (iff ofference to pregnant women of any age), using a 1 in 250 risk cut-off, could identify approximately 60% of Down's syndrome pregnancies for a 5% screen positive rate. Over the next decade the Triple test was gradually introduced in some countries. Refinements, (freeβ and free α hCG, gestational age estimated by ultrasound scan, the use of dimeric inhibin A) led to an increase in detection rate to 76% for the same screen positive rate.
First trimester screening became a possibility following the report of an increased nuchal translucency (NT) at 10-11 weeks of gestation in the late 1980's. This, followed by the addition of biochemical markers (free βhCG and PAPP-A) forms the combined test, best carried out between 11 and 13 weeks of gestation. The integrated test involves a two step testing process, a first trimester combined test (NT and PAPP-A), followed by second timester biochemistry testing, with the integrated risk being given after the second test. These first trimester combined, first and second trimester integrated, together with the newer sequential and contingency tests (see Table) claim higher detection for lower screen positive rates.
The aim of antenatal screening for Down's syndrome is to give parents enough information to choose whether to have a screening test to find out if their baby has Down's syndrome, and to allow time for informed decision-making regarding the option of continuing or terminating affected pregnancies. At present all available tests involve detection rates of less than 100%, and varying screen positive and false negative rates. Those women who opt for a diagnostic test need to understand that there is an associated risk for miscarriage.
Detection rates of over 90% with screen positive rates of less than 3% are now possible. The detection rates achieved will depend upon the uptake of the test and the maternal age profile in different populations. Improved quality assurance can make a big impact on raising detection rates and reducing screen positive rates by eg. addressing inaccuracies in the calculation of median values, specifying the correct software, reagents and equipment used, ensuring the request card is filled in accurately with information on maternal weight, smoking, diabetes, ethnicity, gestation from dating scan. The aim of good quality control is to assess how close the result produced is to the true result, and the effect of any bias. Similarly for NT measurements the software, machine specification, trianing and audit are equally important. The questions what should the risk cut off be, or should there be a risk cut off at all, require careful consideration.
The decision on what, if any tests should be offered, when and how, are difficult and controversial. The uptake of screening programmes in Europe has been patchy and a range of tests are used. Monitoring of screening tests is a vital part of the screening programme. In addition to quality control relating to biochemical and ultrasound markers, audit of uptake of the test detection, screen positive, false negative, diagnostic testing, miscarriage, termination and livebirth rates all need monitoring and continually assessing. The aim for a high detection rate with a low screen positive rate needs to be balanced with feasibility and acceptablitity fo the type of test and cost of the programme.
A study, using data from population based EUROCAT registries, on the impact of different prenatal screening policies in 18 European countries for the years 2000-2004 showed that overall 68% of Down's Syndrome cases were detected prenatally but with a wide range of detection rates (0-95%) between countries. 88% of prenatally detected cases results in termination of pregnancy. Countries with a policy for first trimester sreening had the highest detection rates and countries with no official policy the lowest (www.eurocat.ulster.ac.uk). A recent study from Denmark (BMJ 2008:337:a2547) showed that following the introduction nationally of the first trimester double test, the number of infants born with Downs Syndrome halved and there was a sharp decline in the number of invasive tests.
Screening for Down's Syndrome, and the question does it cause more benefit than harm, is controversial. Annually screening affects millions of pregnancies world wide; unaffected fetuses are miscarried following invasive testing, there is criticism that some health care professionals appear not to understand the screening process, that counselling is unduly negative and that some women find it hard to understand the concept of risk calculation. Large resources are spect monitoring screening programmes and on researching different types of test to find the most effective, efficient and cost effective one. There has been less focus on the psychological consequences of screening, on quality of life for people with Down's Syndrome and support for their families (www.down-syndrome.org/research-practice).
The future for prenatal detection of Down Syndrome is in non-invasive prenatal diagnosis (www.phgfoundation.org). Cell free fetal nucleic acid is present in maternal blood from around 7 weeks of gestation and using molecular techniques the presence of extra chromosome 21 material can be detected. When, after full evaluation, this is introduced into practice women will be able to opt to know if their baby has Down Syndrome without the risk of miscarriage associated with invasive testing. This is a major step forward, but the challenge will be to ensure that women understand the implications of such a test, and that for each woman the benefit outweighs the harm.
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Screening Test
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Components
(all include maternal age)
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Timing of Test and Result
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Nuchal translucency (NT)
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NT
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First trimester
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Combined test
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NT + hCG + PAPP-A
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First trimester
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Double test
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hCG, uE3
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Second trimester
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Triple test
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hCG, uE3, AFP
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Second trimester
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Quadruple test
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hCG, uE3, AFP, inhibin A
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Integrated test
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Combined (BT + PAPP-A) at 11-14 weeks, followed by quadruple test
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First and second trimester, result given in second trimester
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Sequential screening
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Combined test at 11-14 weeks, followed by quadruple test
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First and second trimester, provides first-trimester results and offers the option for early invasive testing or additional serum screening in the second trimester
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Contingency screening
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Combined test at 11-14 week, followed by quadruple test
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First and second trimester. First trimester results divided into high risk (offer of invasive testing), low risk (no further testing), and intermediate risk (proceed to second trimester testing).
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Assisted Reproduction Technique and Congenital Abnormalities: A Small Risk and a Great Prevention
Matorras R
Assisted reproductive techniques (ART) are increasingly employed in western countries. Currently between 1 and 4% of newborns in many countries are the result of ART. ART have two opposed repercussions in the health of newborns that we will analsye in our presentation. First of all, ART can have a negative impact on the health of newborns. Some of such adverse consequences are clearly related not truly with ART, but with the previous conditions present in parents. The following conditions of the mother conceiving with ART can have an adverse effect on the health of the newborn:
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1.
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Maternal age. It is well known that increasing maternal age carries a high risk of miscarriage, cromosomopaties, preterm delivery and fetal growth retardation, among other perinatal complications. Since mean age of women applying for ART is higher than unselected women, no wonder that such complications are increased. |
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2.
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Uterine abnormalities. The presence of uterine abnormalities such as myomas, uterine malformations, cervical incompetence, previous uterine surgeries is higher in women applying for ART. The aforementioned conditions are also associated with miscarriage, preterm delivery and fetal growth retardation, and can be responsible for these problems in ART newborns. |
| 3. |
Also, on occasions, some hereditary condition present in the mother can be transmitted to the infant. |
Also some genetic abnormality present in the father (especially linked with a severe male infertility factor) can be transmitted to the child, especially if he is of male gender.
On the other hand ART procedures can have two implications on the health of newborns: one of them very well known, and the other under debate.
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1.
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ART are asociated with a remarkably increased risk of multiple pregnancy, and especially of high order multiple pregnancy. Depending on the technique, the embryo policy transfer or the ovarian stimulation protocol the rates differ considerably. The impact of multiple pregnancy and high order multiple pregnancy on preterm rate and low birth rates are well known. |
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2.
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There is some concern regarding the possibility that ICSI techniques can be associated with an increased risk of some epigenetic abnormalities such as Angelmann Syndrome. It is not clear if such association, if any, is due to some pre-existing condition in the progenitors, to the specific ICSI technique, or to the embryo culture media. |
Regarding the aforementioned risk situations a number of strategies can de done: discouraging pregnancy (with own oocytes) at advanced ages, discouraging pregnancy at very advanced maternal ages, actively looking for uterine abnormalities and their correction, and actively searching for genetic abnormalities in both the male and the woman. On the other hand, adopting a conservative embryo transfer poicy, as has been done in a number of countries, either folllowing scientific associations or legal regulations, has dramatically reduced the number of multiple pregnancies.
However, ART techniques have a much more beneficial effect on infant health:
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1.
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ART techniques can be employed to avoid the risk of tranmission of some infectious disease to the infant (and to the mother), by means of a washing of the sperm. Such procedure is very well standardised |
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2.
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When donor oocytes are employed, since donors are young, the risk of cromosomopaties id decreased. |
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3.
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Finally, with the implementation of Preimplantation genetic Diagnosis, it is perfectly possible now to avoid the transmission to every single gene genetic disease to the newborn. With such procedure the following disease are routinely avoided:
Spinal Muscular atrophia
Tay-Sachs Disease
Cystick fibrosis
Beta-talasemia
A Hemophilia
B Hemophilia
Duchenne muscular distrophy
X fragile syndrome
Myotonic distrophy
Achondroplasia
Charcot-Marie-Tooth disease
Amiloid polyneuropathy
Huntington disease
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The PGD procedure consists of obtaining embryos during a standard in vitro fertilisation procedure, and subjecting the embryos to a blastomere biopsy. After obtaining the blastomeres, they are subjected to PCR analysis, and if the embryo is found to be healthy, it is transferred to the uterine cavity, whereas if it is abnormal, it is discarded. This way the risk of a severe monogenic disease in teh offspring is avoided. Such technique represents a dramatic change in the reproductive life of parents with a number of hereditary disease, who now can face fertility without risk for their children.
Quality of Genetic Services in Europe
Ibarreta D
Molecular diagnosis of genetic diseases has rapidly moved from the laboratory into medical use and the quality issues have raised concerns. While genetic services in Europe are based on high quality scientific know-how, there were technical errors and poor reporting detected, caused by a lack of structuring and the absence of a common European objective to provide quality services. Diverse and heterogeneous quality schemes, lack of reference systems and differing Member State (MS) regulations, have added to the overall disorganisation and fragmentation of services.
The lack of an adequate quality assurance system for genetic testing has, in the short term, important consequences for the person tested and his/her family and, in the long term, it may increase public mistrust in biotechnology and in the capacity of public authorities to ensure proper governance of biotechnology. A continued support will depend on the capacity of public authorities to ensure proper governance of the use of genetic information. Action at EU level for improvement concerning organisation an defragmentation has already improved the overall situation and continues to do so.
In 2000, a Temporary Committee of the European Parliament focused on the implications of human genetics and other advanced medical technologies was established. The final report of this Committee, though never adopted, recognised that there was an increasing trend for samples for genetic tests to cross international boundaries and that this highlighted the need for an international approach to harmonising Quality Assurance. To this end, it was recommended that:
- international data should be collected on the current state of genetic testing services and Quality Assurance schemes;
- areas for potential co-operation that would lead to developing international standards should be identified, such as proficiency testing and interpretative guidelines;
- international collaboration for the testing of rare conditions should be encouraged and facilitated.
The main European effort in this area has been the creation of EuroGentest (www.eurogentest.org), a Network of Excellence funded under the 6th Framework Programme for Research. It was launched in 2005 with the aim to develop the necessary infrastructure, tools, resources, guidelines and procedures that will structure, harmonise and improve the overall quality of EU genetic services, which can interact with, stand as a model for, or help to achieve similar services on other continents. This is achieved by bringing together, in a real longterm partnership, experts and expert centres available in Europe engaged in different aspects of testing, including researchers, small and medium enterprises (SMEs), testing laboratories, quality management and public health experts, ethicists, lawyers, sociologists, educational authorities and consumers.
EuroGentest has wider implications for European healthcare. An estimated 30 million people now suffer from a genetic disease within the enlarged community. Both new and existing member states find genetics causing an increasing burden upon their healthcare systems, by the latest estimates 500 million euros. Through EuroGentest, a framework for finding cost-effective solutions could be potentially supported. This is complemented by the activity of another EC funded network from January 2006, the Public Health Genomics European Network (PHGEN) (http://www.phgen.nrw.de). The second stage of this network, PHGEN II, has been recently launched. Guidelines for the use of genetic testing and information in health care at European level will be developed.
The European dimension needs to be set in a more global context. Genetic testing is offered internationally, through both public and private sector services, and there is evidence that samples and data are being exchanged across borders, between different jurisdictions. This expanded use and "internationalisation" of genetic testing raises novel issues and remains an increasing trend moving from the restricted world of rare disease genetics to the wider applications of suceptibility testing or pharmacogenetics or gene-expression profiling. These services are being provided under widely varying conditions, heterogeneous quality scehemes, and very different regulatory frameworks.
The most important international acievement in terms of quality of genetic testing at international level is perhaps the work on quality assurance carried under the auspices of the Organisation for Economic Co-operation and Development (OECD). There was a workshop held in February 2000 by the OECD, Genetic Testing: Policy Issues for the New Millennium, where it was agreed that urgent steps should be taken to develop international, compatible best practice policies for genetic test validation, including QA and accreditation and to explore ways to improve genetic training for professionals and counselling and information supplied to the public. The meeting report recommended a comparative analsyis of emerging patterns in the organisation of genetic services and quality assurance systems across OECD countries to facilitate an understanding of the factors influencing the availability of tests and services and the policies to be developed to meet the expected increase in demand. This was followed by a survey of genetics laboratories across 18 OECD member countries that confirmed the steady growth of molecular genetic testing and its widespread availability, revealing a significant international trade in the field. Sixty four percent of the molecular genetic testing laboratories reported that they either received or exported specimens across their national border. The survey also identified some shortcomings in the quality assurance of these services. An international group of experts convened by the OECD worked over several years to produce a set of Best Practices Guidelines for Quality Assurance in Molecular Genetic Testing. The OECD guidelines were adopted in 2007 and are a political commitment on the part of member countries, focusing on quality assurance in molecular genetics including direct-to-consumer genetic tests. The guidelines include a minimum standards for laboratories to follow for quality assurance so that patients can be reassured of the services provided, even from abroad. The guidelines propose that informed consent to test should be the norm; pre- and post-test counselling should be available; advertising and technical claims should be accurate; information regarding the clinical and analytical validity of tests should be made available; laboratories should be accredited to international standards and take part in proficiency testing in a public manner; reporting should be done in patient and family centres; personal genentic information is to be protected and personnel performing tests should be properly qualified and trained The European Commission in collaboration with Member States has actively contributed to the drafting of these guidelines.
Other international bodies such as the Council of Europe and the United Nations have discussed genetic testing in a global context and some of the agreements reached highlight the issues of quality of these tests.
The Council of Europe's Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology (also called The Convention on Human Rights and Biomedicine) has an Additional Protocol concerning Genetic Testing for Health Purposes, setting down principles relating to the quality of genetic services, prior information and consent and genetic counselling. It lays down general rules on the conduct or genetic tests, calling for measures to ensure that genetic services are of appropriate quality; a quality assurance programme implemented in each laboratory; that laboratories are subject to regular monitoring; that tests meet generally accepted criteria of scientific validity and clinical validity; and that the persons providing genetic services have appropriate qualifications to enable them to perform their role in accordance with professional obligations and standards. The protocol also deals with direct-to-consumer genetic tests, a market which seems to be growing rapidly. It specifies the conditions in which tests may be carried out on persons not able to consent. Also covered are the protection of private life and the right to information collected through genetic testing. Finally, the Protocol touches on genetic screening.
Another body which has played a role in the development of international standards for genetic testing is UNESCO. It has adopted an International Declaration on Human Genetic Data which addresses quality issues, calling for the necessary measures to ensure the accuracy, reliability, quality and security of the genetic data and the processing of biologicial samples.
Genetic testing, and its scientific, ethical, legal and social implications are being debated both nationally and internationally. Discussions on the need for new legislation or, in some cases, a review of existing legislation are on-going and many activities at European level addressing genetic testing and in particular regarding its quality and performance assurance are taking place. Without wishing in any way to interfere with Member States' competence regarding genetic testing, the European Commission intends to continue to contribute to a co-ordinated and coherent framework for the use of genetic testing in the EU.
Ethical and Legal Issues on prenatal Diagnosis and Genetic Counselling in Europe
Romeo C
Concept and Relevant Aspects
From an ethical and legal point of view genetic counselling raises a variety of interesting issues, not just because of its role - in a strict sense - of providing and evaluating genetic ifnromation, but also due to the tests that are performed and the possible decisions patietns can make with this information.
Genetic counselling is compased of a number of steps, all of which raise a variety of different ethical and legal concerns:
1. advice of the appropriateness of submitting oneself to certain diagnostic tests and the decision whether or not to undertaken them;
2. actual performance of the tests, which will differ depending upon the time at which they are conducted and the aims pursued in light of
the results;
3. communication and evaluation (advice in the strict sense of the term) of test results; and
4. decisions made in light of the information.
From a legal standpoint, one first has to examine the criteria afforded by current European domestic laws and international statement regarding the lawfulness of the different actions and the measures that can be taken with response to genetic counselling. In addition, it is also important to examine how these laws deal with responsibility for wrongful actions. Thus, we will examine these matters in light of various national rules (Cyprus, France, Germany, Italy, Norway and Spain, among other), as well as various international documents (the World Health Organisation [WHO] report concerning "Proposed International Guidelines on Ethical Issues in Medical Genetics Services" [1988], Council of Europe [Convention on Human Rights and Biomedicine, ECHB 1997] and Recommendation on "Prenatal Genetic Screening, Prenatal Genetic Diagnosis and Associated genetic Counselling [1990]) and UNESCO (Universial declaration on Human genome and Human Rights, UDHGHR [1997] and University Declaration on Human genetic Data [2003]), among others.
General Framework
Consultatation normally begins in two alternatives: in the context of reproduction-related decisions. Antenatal diagnosis is the range of associated diagnoses that are given either prior to the decision of having children - preconception and preimplantation diagnosis - or during the course of the pregnancy, as is the case with prenatal diagnosis. Hence, persons who seek this counselling tend to be couples (married or otherwise), although only one person may be involved (particularly in preconception diagnosis, but also in preimplantation if the transfer of embryos to a single woman without a male partnew is permitted).
The second one is postnatal diagnosis, and it relates more directly to the possibilities of treating or preventing hereditary illnesses in newborn babies, children and even adults. By first determining the family history regarding the transmission and/or appearance of genetic abnormalities, and then by investigating the couple themselves, the necessary data for each of these diagnoses is obtained. Genetic analysis (in the oocyte or in the in vitro embryo) through a variety of diferent test in which other qualified specialist, particularly gene biologists, participate alongside the doctor, is commonly used to investigate couples.
At this point it is important to remember that all international documents on human genetics proclaim as one of their main principles a ban on the discrimination of human beings based upon his or her genetic characteristics ECHB, art. 11; UDHGHR, art.6).