Pre-implantation genetic diagnosis enables the genetic testing of embryos in the process of in vitro fertilisation before they are transplanted.
						The method raises ethical questions, affects different societal interests and therefore represents a continuing legislative challenge.
						In 2011, balancing individual and societal interests with regard to the handling of embryos and discrimination against those affected, a majority of the German Bundestag voted for a strictly limited authorisation.
						To date, with around 300 applications per year, the number of people making use of PGD corresponds to the estimations formulated in the legislative process.
						The further development depends on questions regarding reimbursement, the number of indications approved by the PGD Ethics Committees and the clarification of
					open legal questions

Albrecht, Steffen

Grüber, Katrin

English

KITopen

BÜRO FÜR TECHNIKFOLGEN-ABSCHÄTZUNG BEIM DEUTSCHEN BUNDESTAGStatus quo and developments of pre-implantation genetic diagnosis1www.tab-beim-bundestag.de ISSN-Internet 2364-2645TAB-Fokus no. 21 regarding report no. 182 September 2019Client Committee on Education, Research and Technology Assessment +49 30 227-32861 bildungundforschung@bundestag.dedistinguished: monogenic disorders, i. e. diseases caused by a single gene (e. g. Duchenne muscular dystrophy), and aneuploidies or translocations, i. e. changes in the number or arrangement of chromosomes.The challenge for society is to define the legitimate use of this method of reproductive medicine, adequately taking into account the different interests affected by PGD. On the one hand, PGD as a method of selecting embryos is al-most inevitably associated with discarding embryos. It also requires IVF to be carried out with all its burdens on the woman, even in cases where a couple would be able to con-ceive children naturally. In addition, there are fears that the decision to consider certain diseases to be unacceptable will also result in a derogatory judgement of those affected by such diseases and thus discriminate against them. On the other hand, affected couples have the desire to have a genet-ically related child who is not affected by a serious genetic disease or chromosomal disorder. Very often, couples seek-ing PGD have experienced multiple miscarriages or have children affected by a disease. By many people, a »trial« pregnancy with prenatal diagnosis (PND) and possible late termination is considered to be more problematic than making use of PGD.Regulation in Germany and EuropeFor the first time, PGD was carried out successfully in Eng-land in 1990. In Germany, an explicit legal regulation was agreed upon comparatively late. Until 2010, PGD was con-sidered to be prohibited by the former Embryo Protection Act. However, the German Federal Court of Justice ruled that certain forms of PGD complied with the law and called for a distinct legal regulation. In 2011, after extensive parlia-Summary › Pre-implantation genetic diagnosis enables the genetic testing of embryos in the process of in vitro fertilisation before they are transplanted. › The method raises ethical questions, affects different societal interests and therefore represents a continuing legislative challenge. › In 2011, balancing individual and societal interests with regard to the handling of embryos and discrimination against those affected, a majority of the German Bun-destag voted for a strictly limited authorisation. › To date, with around 300 applications per year, the number of people making use of PGD corresponds to the estimations formulated in the legislative process. The further development depends on questions regard-ing reimbursement, the number of indications approved by the PGD Ethics Committees and the clarification of open legal questions.What is involvedPre-implantation genetic diagnosis (PGD) is the genetic testing of embryos produced by means of in vitro fertili-sation (IVF). For PGD, several embryos are produced and tested with regard to genetic traits that could lead to serious diseases, disabilities or even death of the embryo or child. Only embryos that do not have disease-related characteris-tics are used to establish a pregnancy.In Germany, PGD is generally prohibited, but permitted under certain conditions. In § 3a of the Embryo Protection Act, the following conditions for an exemption of punish-ment are specified: › the high risk of a serious hereditary disease or › serious damage to the embryo, which is most likely to lead to stillbirth or miscarriage. › There is no list of indications, since – according to the law – each individual case is to be considered with all its particularities. However, two groups of cases can be TAB-Fokus no. 212 Photo page 1: NinaSes/wikimedia.org; Jhagenk/wikimedia.org; BilliTheCat/pixabay.combut only few scientifically founded evaluations are availa-ble. The compilation of available data from various sourc-es (PGD Ethics Committees, publications, media reports) shows an increase in the number of PGD applications over the past few years, but also a total number of approvals that is in line with the expected few hundred treatments. In 2018, according to a media report, slightly more than 300 applications for PGD were submitted, of which approx-imately 90 % were approved.Three groups of stakeholders, each with an own perspective, are essentially involved in the implementation of PGD: the couples, the PGD centres and the PGD Ethics Committees. Couples are usually interested in PGD as a result of their personal history, for example because they have been diag-nosed with a genetic disease or because they have had several stillbirths or miscarriages. They receive information in the course of a human genetic counselling, in a fertility centre, through self-help organisations of affected persons or (in varying quality) via the Internet. Afterwards, they can find contact persons and advice in one of the eleven PGD centres.mentary and public debates, the German Bundestag added a new § 3a to the Embryo Protection Act. In addition to limit-ing the use of PGD to the indications mentioned above, this new article provides for institutional regulations (particu-larly regarding the competence of an Ethics Committee) as well as strict quality requirements (i. a. implementation only by officially approved PGD centres). In 2014, the associated »Order on the Lawful Conduct of Pre-implantation Genetic Diagnosis« (German: »Verordnung zur Regelung der Präim-plantationsdiagnostik« [PIDV]) came into force and corre-sponding regulations at the Länder level followed. Only on this basis, the PGD centres and Ethics Committees were able to start their work.The purpose of the amendment was to create the basis for a strictly limited implementation of PGD in Germany. In this context, a central role is played by the PGD Ethics Com-mittees, which have to check for each application for PGD whether the conditions for impunity are met. In the mean-time, legal action has been taken against negative decisions made by committees. In one case (not yet final), it was decided that the decisions can only be reviewed in court to a limited extent, but that the actual assessment (in this case whether the expected disease is »serious« as defined by law) cannot be made by a court. Another issue under judicial review is whether trophectoderm biopsy – current-ly the standard procedure for PGD, for which only cells of the outer cell layer of the embryo are removed – requires the approval of a PGD Ethics Committee. Moreover, the German Federal Social Court determined that the costs of a PGD are not cov ered by the statutory health insurance scheme.Within Europe, PGD is legally possible in all EU countries, even if explicit legal regulations do not exist in all countries. A possible use of PGD for sex selection without medical in-dication is prohibited throughout the EU. Apart from that, there are sometimes considerable differences with regard to the spectrum of admissible indications and the institutional implementation – with regulation in Germany being one of the more restrictive ones. Several countries have set up spe-cific authorities to control PGD practice. These authorities are responsible for approving PGD centres and for determin-ing admissible indications (e. g. the largely independent UK Human Fertilisation and Embryology Authority). In some countries, it is only up to the couples to decide. In other countries, however, counselling (Switzerland) or approval (France) by medical experts is mandatory.Practical implementation of PGD in GermanyIn the discussion on legal regulation, the expected effects of the law as well as the issue of limiting the use of PGD were discussed again and again. Meanwhile, first experiences, In vitro fertilisationAdministration of hormones to stimulate the ovaries of the womanCollection of oocytes and spermFertilisation of eggsEmbryo at the blastocyst stage(approx. 5 days after fertilisation)Removal of eight to ten cells from the outercell mass of the embryo at the blastocyst stageEmbryo freezing (cryopreservation)Genetic testing of the cellsEmbryo biopsy and genetic testingDecision on implantationSelected embryos are transplanted into the uterus.Embryos with developmental potential remain frozen.Embryos with undesirable genetic traits are discarded. Search for informationPrevious experience of the couple(genetic diagnosis/miscarriage)Information provided by› fertility centres› genetic counsellors› internet sourcesSubmission of documentsCounselling of the couple with regard to› reproductive medicine› human genetic aspects› psychosocial aspectsCase discussion (rejection, when indicated)Counselling at the PGD centreApplication to a PGD Ethics CommitteeSubmission of documentsAssessment and decision by the committee members(rejection, if deemed necessary)Fig. 1  Steps towards PGDStatus quo and developments of pre-implantation genetic diagnosis3Photo page 1: NinaSes/wikimedia.org; Jhagenk/wikimedia.org; BilliTheCat/pixabay.comclinics also offer their services specifically in German. In turn, couples from abroad use the services of German PGD centres.The PGD centres each consist of a human genetic centre and one or more fertility centres. These do not necessarily have to be located at the same site. The centres exchange infor-mation on procedures and experiences at the technical level and work according to common guidelines, but in principle independently of each other. Their respective capacity to car-ry out examinations depends on the financial and technical resources as well as on the experience of the staff. A PGD centre can refuse treatment if there is not sufficient capacity or if the chances of success are considered to be too low from a medical perspective or in view of the Ethics Committee’s decision.With eight members each, the PGD Ethics Committees are interdisciplinary and represent four different medical disci-plines, ethics and law as well as organisations of patients and people with disabilities. They are supported by branch offices and charge fees for the processing of applications (EUR 300 to 3,000, depending on the effort involved and the support-ing institution), whereas their members work on a voluntary basis. In Germany, there are five committees, two of which are responsible for several Länder. Each case is assessed in-dividually by the members of the committees. For this, they mainly focus on the medical indication. In ambiguous cases, however, the personal circumstances are also taken into con-sideration. Thus, it may happen that applications are assessed differently by the same committee, though they are appar-ently based on the same indication. Nevertheless, in order to create a common framework for decisions, the committee members have intensive discussions with each other as well as with the members of other PGD Ethics Committees. For an application to be approved, two thirds of the members must agree.Current lines of developmentFurther development will be influenced in particular by the legal framework and its interpretation by courts, PGD Ethics Committees and PGD centres. Other influencing factors are framework conditions such as the regulation of reimburse-ment and admissible indications as well as the development of medical research and technology.The legal regulation of PGD is meant to balance individual and societal interests in particular with regard to the handling of embryos and discrimination against those affected. Fun-damental questions such as the regulation of PGD by means of a specific act on reproductive medicine instead of the cur-rent criminal law provisions given in the Embryo Protection Law or the different legal treatment of PGD and PND are In the course of the multi-stage counselling and deci-sion-making process, some of the initially interested couples (between 50 and 88 %, depending on the survey used) refrain from submitting an application to a PGD Ethics Committee. For this, the following factors might play a role: › the intensity of the couple’s desire to have children and their attitude to late termination – for some couples, pregnancy with PND is an alternative to PGD, especially as an additional PND is also recommended for PGD; › the costs of PGD, which are not assumed by health insur-ance companies (a total of approx. EUR 15,000 to 20,000); › the uncertainty of success in view of the effort involved (potentially with several treatment cycles) and the risks of the treatment, especially for the woman; › the examination procedure of the respective PGD Ethics Committee, which is perceived as an obstacle.For some couples, going abroad is an alternative, because access to treatment abroad is easier or geographically near-by, or because more options are available. Corresponding In vitro fertilisationAdministration of hormones to stimulate the ovaries of the womanCollection of oocytes and spermFertilisation of eggsEmbryo at the blastocyst stage(approx. 5 days after fertilisation)Removal of eight to ten cells from the outercell mass of the embryo at the blastocyst stageEmbryo freezing (cryopreservation)Genetic testing of the cellsEmbryo biopsy and genetic testingDecision on implantationSelected embryos are transplanted into the uterus.Embryos with developmental potential remain frozen.Embryos with undesirable genetic traits are discarded. Search for informationPrevious experience of the couple(genetic diagnosis/miscarriage)Information provided by› fertility centres› genetic counsellors› internet sourcesSubmission of documentsCounselling of the couple with regard to› reproductive medicine› human genetic aspects› psychosocial aspectsCase discussion (rejection, when indicated)Counselling at the PGD centreApplication to a PGD Ethics CommitteeSubmission of documentsAssessment and decision by the committee members(rejection, if deemed necessary)Fig. 2  Stages of PGD4 Büro für Technikfolgen-Abschätzung beim Deutschen Bundestag Neue Schönhauser Straße 10, 10178 Berlin | buero@tab-beim-bundestag.de | Tel.: +49 30 28491-0September 2019TAB-Fokus no. 21TAB report no. 182Aktueller Stand und Entwicklungen der PräimplantionsdiagnostikSteffen Albrecht, Katrin GrüberWebsite of the projectwww.tab-beim-bundestag.de/en/ untersuchungen/u20820.htmlProject manager and contactDr. Steffen Albrecht+49 30 28491-111albrecht@tab-beim-bundestag.deAktueller Stand und Entwicklungen der PräimplantationsdiagnostikSteffen Albrecht Katrin GrüberEndbericht zum MonitoringSeptember 2019Arbeitsbericht Nr. 182The Office of Technology Assessment at the German Bundestag (TAB) advises the German Bundestag and its committees on questions of scientific and technological change. TAB has been operated by the Institute for Technology Assessment and Systems Analysis (ITAS) of the Karlsruhe Institute of Technology (KIT) since 1990. It has been cooperating with the IZT – Institute for Futures Studies and Technology Assessment and VDI/VDE Innovation + Technik GmbH since September 2013. The Committee for Education, Research and Technology Assessment decides on TAB’s work programme, which also in- cludes subjects proposed by other parliamentary committees. The standing »TA Rapporteur Group« consists of the Chair-man of the Committee Dr. Ernst Dieter Rossmann (SPD), and one member from each of the parliamentary parties: Stephan Albani (CDU/CSU), René Röspel (SPD), Dr. Michael Espendiller (AFD), Prof. Dr. Andrew Ullmann (FDP), Ralph Lenkert (Die Linke), Dr. Anna Christmann (Bündnis 90/Die Grünen).a resulting list of indications. In addition, there is a need for research with regard to studies on couples interest in PGD, on the quality of available information and counselling as well as on experience made with PGD. Moreover, the discus-sion about aneuploidy screenings illustrates that studies on medical quality criteria of PGD and associated IVF proce-dures represent a desideratum.The existing legal provision allows PGD to be carried out while, at the same time, strictly limiting its application. The situation could change if courts would reinterpret the Embryo Protection Act. Furthermore, a legislative initiative would be required to amend the reimbursement scheme. It seems to be recommendable to continue observing the rapidly ad-vancing development of reproductive medicine, genetic diagnosis and therapy and, if necessary, to take legislative action. The implications of PGD affect fundamental societal issues and values. This is why these implications should be addressed again and again in the public political debate.being discussed. With regard to the question of the allowed number of eggs to be fertilised, a practice of fertilising more than the three eggs mentioned in the law has developed. In this respect, however, explicit clarification is called for.An important change in the framework conditions would be to find an arrangement regarding reimbursement by the health insurance companies. Such an arrangement could in-volve a change in the number of applications. However, this could only be realised by modifying social legislation. Fur-thermore, the uncertainty and complexity of the approval procedure as well as the treatment itself represent limiting factors for PGD practice. Another important framework condition is the number of admissible indications. In many countries, the initially limited range of indications has been extended over time. In Germany, the PGD centres are cur-rently discussing the assessment of late onset diseases such as Huntington’s disease and of genetic variants associated with a strongly increased probability of breast cancer. A particular question in this context are tests with regard to aneuploidies in the form of screenings (as a service for all IVF treatments). In response to demands for a general screening, it is argued that this would not be consistent with the objective of limiting the use of PGD. Moreover, the medical benefit with regard to improving the success of IVF treatments is questionable.Last but not least, technological developments in the field of reproductive medicine and genetic diagnosis can funda-mentally influence the practice of PGD. Next-generation se-quencing (NGS) allows to examine the entire genome using sequencing techniques and is being used more and more of-ten. In this way, it is no longer necessary to separate the test for monogenic disorders from that for chromosomal anom-alies, since both can be carried out in one run only and in a relatively short time. However, these tests reveal more addi-tional findings, the handling of which requires clarification.Options for actionDetailed, up-to-date and publicly available data on the ap-plication of PGD are required to provide monitoring pos-sibilities for Parliament and civil society. In this context, however, consideration should be given to the possibility of 

Status quo and developments of pre-implantation genetic diagnosis. TAB-Fokus

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Status quo and developments of pre-implantation genetic diagnosis. TAB-Fokus

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