Preimplantation Genetic Diagnosis

I. Medical and scientific aspects

The term "preimplantation genetic diagnosis" (PGD) describes methods of testing embryos generated by in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). The genome of one or two cells of a several-days-old embryo – usually during the so-called eight-cell stage (blastomere stage), i.e. about three days after fertilisation  – is tested for certain mutations or chromosomal abnormalities that may result in a disorder, before the embryo is transferred to the uterus. PGD can also be used to identify other than disease-relevant characteristics, such as the embryo’s sex, the presence of a certain disability or the embryo’s suitability as an organ or tissue donor for a living sibling affected with a disease. In some countries, PGD is already being applied for these purposes. More indications for the application of PGD can be found in international medical literature: "high" maternal age, i.e. over 35 years, repeated unsuccessful IVF treatments, recurrent miscarriages and ICSI. However, a study published in 2007 in the New England Journal of Medicine claims that IVF with subsequent PGD does not lead to higher pregnancy rates.

In international medical literature, the indications for the application of PGD are: "high" maternal age, i.e., over 35 years, recurrent miscarriages, which may be due to chromosome disorders, and repeated ineffective treatment by in vitro fertilisation (IVF). In addition, PGD treatment is indicated in case of existing serious hereditary problems in the family due to monogenic diseases such as cystic fibrosis, myotonic dystrophy, spinal muscular atrophy, sickle cell disease, β-thalassemia, Huntington's chorea, epidermolysis bullosa or marker-X Syndrome. In the case of multifactorial diseases, many genetic risk factors in many embryos would have to be studied to find an embryo with a low risk for such a disease, which is currently not feasible.

In the case of the originally employed methods the one or two cells which are removed from the embryo for testing are totipotent at this stage. It can thus be assumed that, given certain conditions, they could each develop into an individual embryo. As the destruction of totipotent cells is considered as ethically and legally problematic (see below), the removal of cells (biopsy) is increasingly performed five to six days after fertilisation, i.e. at the so-called blastocyst stage. According to the current state of research, these cells are no longer totipotent, but merely pluripotent. Furthermore, it is assumed that this form of biopsy is less invasive because the trophectoderm of the blastocyst is examined, the cells of which subsequently develop into the placenta and amniotic membrane. Another advantage is that a smaller proportion of the total cell mass is taken, but in total more cells can be examined, which increases the certainty of the diagnosis.

The technologies necessary to perform PGD were mostly developed in the U.S., Great Britain and Belgium at the end of the eighties/beginning of the nineties. The first applications were made in Great Britain, where the first child after PGD testing was born in 1990. Human leukocyte antigen (HLA) typing to select an embryo as possible immunocompatible tissue donor for a sibling was first described in 2001.

According to the European Society of Human Reproduction and Embryology (ESHRE), the most common reasons for PGD were the two non-treatable neuronal disorders Huntington's Disease and Myotonic Dystrophy. Within the preparation of the German PGD Regulation (PIDV) based on the experience gained abroad, it was estimated in 2014 that 200 to 300 applications for molecular genetic testing would be made each year. According to a report by the Federal Government, this expectation was achieved for the first time in 2018 with round about 300 applications.

The PGD-related methods of preconception or prefertilisation diagnosis are less controversial than the genetic testing of embryos. They involve the genetic analysis of the polar bodies of the woman’s oocytes prior to fertilisation. This method thus only provides information on the maternal genotype. Moreover, because the costs are higher and two biopsies have to be done instead of one compared to blastomere or blastocyst biopsy, polar body diagnostics are increasingly replaced by other types of PGD. Preconception diagnostic procedures could be complemented by a preconceptional genetic analysis of the male spermatocytes. However, the main difficulty of this method lies in the fact that the spermatocytes are generally being destroyed in the procedure and are thus no longer available for later fertilisation of an oocyte. Currently, procedures aiming at artificially duplicating the spermatocytes prior to their genetic analysis are being clinically tested: thus, the genetic material of the first spermatocyte could be used for testing and the second, identical spermatocyte for fertilisation. There are also physical methods that allow sperm to be examined for the sex chromosome. This makes it possible to exclude certain sexchromosome-linked diseases.

Physical methods allow the identification of sperms carrying Y-chromosomes, as they vary in mass to those carrying X-chromosomes due to different DNA contents. This could be used in the context of fertilisation involving sex selection to avoid X-linked genetic diseases.

If PGD and the subsequent transfer of the embryos to the uterus result in a pregnancy, the diagnostic findings of PGD are usually checked by the (non-invasive and/or invasive) methods of prenatal diagnosis (PND).

The risks of PGD for the woman can be compared to those of extracorporeal fertilisation by IVF/ICSI without PGD. On the one hand, the removal of the oocytes and the transfer of the embryos following PGD may bring about infections. On the other hand, there is an increased risk of ovarian hyperstimulation syndrome. This is due to the fact that, as a general rule, more oocytes have to be generated for PGD than for IVF/ICSI without PGD, given that many embryos are not transferred because of unsuccessful biopsies, diagnostic findings or irrelevant results of the testing. Therefore, hormonal stimulation is usually set at a higher level when PGD is used than in the context of in vitro fertilisation without subsequent PGD. In addition, there are risks for mother and child related to multiple pregnancies, which increasingly occur in the context of extracorporeal fertilisation. Moreover, the woman or the couple may have to face high psychological strain as a result of hormone treatments and also of hopes and fears related to the success of the method.

The embryo faces the risk of not being transferred and of being destroyed in the case of abnormalities discovered, irrelevant testing results or false diagnosis. Further risks include the embryo’s destruction during the removal of cells for testing and the increase in multiple pregnancies. Some studies prove that IVF embryos are more likely to develop malformations.

In addition to PGD, procedures are being studied which, by means of the significantly improved possibility of human gene editing, shall alter the DNA of embryonic cells showing hereditary disposition for monogenic diseases such as myotonic dystrophy or Huntington’s disease. While until now such embryos are discarded within the course of PGD they could be employed after a successful alteration of their genetic sequences which includes, among others, the cutting out of "defective" genes. These procedures are so far experimental. Moreover, the related alteration of the human genome is subject to legal restrictions and ethical concerns.

II. Legal aspects

Whether the application of PGD is legally permitted or prohibited strongly depends on the legal definition of embryo protection in the respective country.

1. International regulations

Council of Europe
The 1997 Council of Europe's Convention on Human Rights and Biomedicine – which has not yet been signed by Germany - authorises diagnostic testing on the human genome under certain conditions. PGD, however, is not explicitly regulated. In 2004, the European Parliament issued the directive 2004/23/EC on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. This directive had to be enacted by the member states until 7th April 2006.

A comparison of existing laws and directives in European countries on the application of PGD shows that the legal protection of the embryo is organised in very different ways.

2. Regulations in individual countries

In Germany, the provisions for PGD are regulated in the framework of the embryo protection act (Embryonenschutzgesetz (ESchG)). With the law of regulation of the preimplantation genetic diagnosis (Präimplantationsdiagnostikgesetz (PräimpG)), which got approved by the German parliament on November 21st 2011, and the change of the embryo protection act related to it, and despite its fundamental prohibition, the genetic examination of the pluripotent cells of the embryo in vitro, before its intrauterine transfer, within exceptions and tight limits, is declared not illegal. Hence there is an explicitly legal regulation of PGD for the first time. Applying PGD on the basis of the new law is regulated by the ordinance on the legitimate implementation of preimplantation genetic diagnosis (Präimplantationsdiagnostikverordnung (PIDV)), which came to force on February 1st 2014.

In both its original version of 1991 and its revised version of 2001, the embryo protection law doesn’t comment explicitly on PGD.  Since the beginning of the debate, however, it is beyond dispute that on the basis of the embryo protection law, it is forbidden to carry out PGD on cells extracted in their blastomere stage which are hence totipotent. According to § 8 of the ESchG, each individual totipotent cell has the status of an embryo that is protected by the ESchG. The removal of totipotent cells from an embryo is prohibited under Section 2 (1) of the ESchG, since the removed embryo is not removed and used for the purposes of its own preservation. The situation hasn’t changed with the new law expansion. The discussion on PGD, which found expression in the expansion of the embryo protection law, was rather concerned with the question whether carrying out PGD on blastocysts is allowed by the German legislation. Blastocysts are no longer totipotent cells; they are only pluripotent, and can no longer evolve into a human being, but only into different human organs. In reality, PGD was not carried out in Germany until 2010 due to the existing uncertainties. With the world wide establishment of PGD in the reproductive medical practice, there was a demand for an explicit regulation of PGD in the context of a law of regulation of reproductive medicine, from which the embryo protection law should rise.

The district court of Berlin decided in May 2009 that the PGD of pluripotent cells of the embryo which are obtained by trophoblast biopsy does not violate any legal rule of the Embryo Protection Act if it is carried out with the purpose of inducing a pregnancy and to screen out impending hereditary diseases. After the public prosecutor’s office had initially appealed on points of law, the Federal Court of Justice confirmed this decision on July 10th 2010. Given the mentioned requirements (with the aim of bringing about a pregnancy and examining trophoblasts in the blastocyst stage to exclude any serious genetic diseases), carrying out PGD is not subject to prosecution.

On July 7th 2011, members of the German Bundestag voted by a majority for a draft law according to which PGD should be permitted, as far as there is high probability for serious genetic disease or in cases in which miscarriage or stillbirth are likely. A clarification of the terms "high probability" and "serious genetic disease" is missing. The approval of the law by the Federal Council took place on September 26th. The law is effective since December 8th 2011. For both cases described in the legislative text, the written consent from the potential parents must be submitted. Moreover, PGD is only allowed to be implemented when the parents become well informed about the medical, psychic and social consequences of the diagnostic, and when an ethics committee examined whether the mentioned requirements are met. In November 2020, a verdict of the German Federal Administrative Court concretised that ethics commissions are not granted a scope of assessment and that their decisions can be fully judicially reviewed by courts. For the implementation of PGD, only qualified physicians in licensed centres are authorised to perform preimplantation genetic diagnosis.

Prior to the decision of the German parliament, many expert committees had commented the topic. Both the German Ethics Council and the German Medical Association have declared themselves in favour of a legalisation of PGD implementation within tight limits.

Proponents of the new regulation are hoping for clarification regarding the contradiction in the legality of PGD and PND in the mother's womb. Following the previous regulation, the woman can decide to terminate pregnancy if a genetic disorder is diagnosed, while PGD, as a method which aims at the same result, but is performed prior to implantation and thus at an earlier moment, is not legal. It is argued that the background is the same in both cases, i.e. the anticipation of unacceptable postnatal burdens. This comparison is rejected by opponents of the new regulation who argue that the initial situations are different and therefore have to be assessed in a differentiated manner. In their opinion, the interests of life of mother and child are already set against each other in the case of PND, whereas in the case of PGD this situation is created deliberately by the generation of embryos.

On July 11th 2012, the health minister at that time, Daniel Bahr, submitted a draft regulation on the legitimate implementation of preimplantation genetic diagnosis. In this draft, the standards for licensing PGD centres and for the qualification of the doctors who are registered there were specified. Furthermore, the establishment, composition, procedural methods and funding of the ethics committees, which decide on the admission of individual cases to PGD, are regulated. Moreover, the modalities of the establishment and organisation of a documentation centre for the conducted measures in PGD as well as the notification of those measures and their documentation are defined.

The draft law regulation has been criticised from the members of the German parliament and the church. In its statement from November 23rd 2012, the National Ethics Council criticised that the organisational and procedural aspects of the PGD centres and the corresponding ethics committees are ill-defined and to some extent are for the countries to decide upon, so that uniformity, transparency and monitoring possibilities cannot be insured by the lawmaker. The German Medical Association considers the submitted draft inconvertible and proposed some amendments

After a long debate, the German Federal Council eventually agreed to the draft regulation on February 1st 2013, however it required an amendment of the regulation: The German Federal Council demanded that the PGD centres are authorised separately and thus limited to a smaller number. On February 19th 2013, the German Cabinet passed a modified version of the regulation, which meets the requirements of the German Federal Council. The regulation came to force twelve months after it was passed in order to give the federal states enough time for the establishment of the necessary structures. 

Since 2014, five ethics committees for preimplantation diagnostics have been set up across Germany. The Ethikkommission Nord, responsible for applications from Hamburg, Bremen, Schleswig-Holstein, Lower Saxony, Brandenburg and Mecklenburg-Western Pomerania, is located at the Ärztekammer Hamburg. Since 2015, the Ethikkommission Süd, responsible for the states of Baden-Württemberg, Hesse, Rhineland-Palatinate, Saarland, Saxony and Thuringia at the Landesärztekammer Baden-Württemberg in Stuttgart, has decided on applications for PID. The Ärztekammer Nordrhein is responsible for the ethics committee for the state of North Rhine-Westphalia. The ethics commissions for the states of Berlin and Bavaria, on the other hand, are located at the Berlin State Office for Health and Social Affairs and the Bavarian State Ministry for Health and Care. Since no PGD center is currently being considered in Saxony-Anhalt, the federal state has decided not to set up an ethics committee. A total of twenty PID centers were approved in Germany in 2020, six of them in Bavaria. The actions carried out by the centres as part of a PGD are documented by the Paul-Ehrlich-Institut (see module Central office for PGD at the Paul-Ehrlich-Institut), the Federal Institute for Vaccines and Biomedicines.

In its coalition agreement of 2021, the German government´s coalition aims to fully cover the costs of PGD.

The Austrian Law on Reproductive Medicine (Fortpflanzungsmedizingesetz – FMedG) only authorises the testing of cells capable of development if this is, in the light of current medical knowledge and experience, necessary for the establishment of a pregnancy (FMedG Art. 1 § 9).

The governing parties ÖVP and SPÖ filed a proposal for an amendment in November 2014. It resulted in the Fortpflanzungsmedizinrechts-Änderungsgesetz 2015 – FMedRÄG 2015 that came into force on the 24th of February, 2015. The prohibition of PDG remains valid. In some cases it is possible to test for serious hereditary illnesses with help of PDG embryos before their insertion in the uterus. An exception to the prohibition is granted if the genetic disposition of a parent causes a risk of death or miscarriage or a risk of a serious, non-treatable hereditary illness for the new-born that adds the risk of serious brain damage or severe pain or thanks to which the child would only survive with intensive medical care. It shall be possible to test embryos for their viability even after three unsuccessful IVF trials or three miscarriages. PDG as assistance for the production of a so-called saviour sibling remains prohibited.

The ban on PGD in Switzerland was partially lifted by a draft law amending the Federal Act on Medically Assisted Reproduction (Reproductive Medicine Act - RMA), which was finally adopted in June 2016 through a referendum. Since then, the analysis of the genetic material of reproductive cells and their selection to influence the sex or other characteristics of the child are permitted in order to identify chromosomal properties that may inhibit the development capacity of the embryo to be created, or if there is no other way of avoiding the risk of transmitting a predisposition for a serious disease. The law states as a condition that it is probable that the serious disease will occur before the age of 50 and that no effective or expedient therapy is available for combating it. A selection of embryos based on their gender or other physical characteristics independent of a medical condition as well as the generation of so-called saviour siblings remains prohibited. 

The number of embryos that may be created per IVF cycle has been increased from three to twelve. The freezing and storage of embryos is also permitted.

The couples for whom PGD would be an option decide independently after detailed consultation whether they would like to carry out the examination. There is a duty to provide advice on the part of the doctors. Neither the costs for PGD nor for the IFV treatment are covered by the statutory health insurances. 

Great Britain
The Human Fertilization and Embryology Act which was passed in Great Britain in 1990 created a legal framework for the handling of in-vitro embryos. PGD and the involved embryo selection are generally permitted in licensed centres. In 2002, the British Department of Health released guidelines for the provision of PGD services. The reasons for requesting PGD include serious genetic disorders, chromosomal disorders and the suitability as a tissue donor for a living affected sibling under certain conditions. A selection in terms of the embryo's sex is strictly regulated: According to the guidancenote 10 of the Code of Practice (9th Edition, 2019) such a selection is allowed to be carried out only in cases where there is a medical indication of a risk for a sex-related hereditary disease.

In France the application of PGD has been regulated by the Code de la santé publique (French Public Health Code). The regulations of PGD stated therein were amended several times by bioethics laws, most recently in 2021. According to these laws, PGD is only permitted in order to prevent serious genetic diseases which are considered untreatable or incurable at the moment of the diagnosis. It may not be applied if the anomaly responsible for the specific disease has not been clearly diagnosed beforehand in one parent or a direct relative. Furthermore, the diagnosis may be applied for the selection of a saviour sibling. The diagnosis may only be conducted in an institution specially accredited for this purpose. 

The Netherlands
In the Netherlands, the Embryo Act came into force on 1st September 2002. It does not provide for a legal ban on PGD. Since 2013, guidelines on PID (Regeling preïmplantatie genetische diagnostik) regulate when and how examinations on the embryo can take place. Sex selection of embryos is prohibited. The diagnosis applied for the selection of a saviour sibling is only permitted if a PGD is indicated for genetic reasons. Since June 2008 it is allowed to sort out embryos which show an increased risk for diseases such as hereditary cancer prior to implantation. The PGD National Indications Committee (Landelijke Indicatiecommissie PGD), whose members are appointed by the professional association of clinical geneticists (VKGN) and the professional association of gynaecologists (NVOG), decides on the approval of new indications in accordance with the guidelines for PGD.

In Belgium PGD is not governed by explicit legal provisions. It is however implicitly regulated under the term "treatment" by the law on IVF embryo research (Loi relative à la recherche sur les embryons in vitro) that became effective on 11th March 2003. In case of medical indications and after submission of a request to the competent bioethics commission, it is carried out in licensed centres. Sex-specific embryo selection is prohibited, with the exception of selection in order to eliminate embryos with sex-linked diseases.

In the USA PGD is governed by State law and thus regulated in very different ways. In most States there are no legal provisions regarding the authorisation and application of PGD. In those States, the area of application extends beyond medical indications and includes sex selection as well as selection according to specific criteria. A study on genetic testing of embryos in the U.S. illustrates that selection is also carried out with regard to the presence of a disability.

III. Ethical aspects

PGD involves the testing of embryos and unfertilised oocytes and, depending on the results of the analysis, their exclusion from the reproductive process before the achievement of a pregnancy is being attempted. Several main emphases can be distinguished in the current debate on the ethical assessment of PGD.

The ethical debate on the methods of PGD centres on the question whether the embryo’s possible rights to protection are being violated by these methods, and if so to what extent. Underlying this discussion is the question of the moment from which rights and protection are assigned to the embryo. This question is not only relevant with regard to the manipulation of the embryo during the biopsy and the inevitable destruction of embryonic cells during the diagnosis, but also and especially when it comes to the possible decision not to transfer the embryo to the uterus due to embryopathy or other undesired characteristics.

Decisive for an assessment of the moral status of the human embryo is the respective underlying ethical concept of protection. Two basic positions can be distinguished. A first position fully transfers the entitlement to protection associated with a human being after birth to the human embryo from its very beginning, i.e. from the fusion of nuclei, due to its personhood. A second position grants the embryo a graduated entitlement to protection depending on its achievement of a certain developmental stage. Possible relevant developmental moments are the nidation in the uterus, i.e. the moment from which an embryo is actually capable of developing, or the formation of the primitive streak which marks the completion of individuation, as from that moment the possibility of a multiple pregnancy can be ruled out. The arguments given in scientific discourse regarding ontological prerequisites for full or graduated entitlement to protection can be assigned to four main categories. In Germany, they are often called SKIP-arguments (from the initial letters of the relevant headwords in German). They are supported or challenged individually, but also in combination, as they complete each other and are interdependent.

  1. Species argument
    According to the species argument, embryos, since they biologically belong to the species Homo sapiens, possess dignity and are thus worthy of protection like all other members of this species. In the sense of equal treatment, they have the same right to life as born human beings.
  2. Continuity argument
    The continuity argument is closely linked to the species argument when it comes to the question of the biological beginning of individual human life. It is based on the assumption that embryos continuously develop and that in the process of their development into a born human being there are no breaks of moral relevance; consequently they have to be afforded the same rights as born human beings.
  3. Identity argument
    The thesis underlying the identity argument states that the embryo’s dignity can be derived from the morally relevant, existing identity between a born human being and the embryo from which he or she has developed after the fusion of spermatocyte and oocyte and from the fact that the born possesses human dignity.
  4. Potentiality argument
    The potentiality argument implies that the fertilised oocyte already possesses the full potentiality to become a born human being. In the natural process of anthropogenesis, the embryo thus has, since its beginning, the potentiality to develop into a personal being and a moral subject. Due to this potential, existing from the beginning, the embryo is worthy of unrestricted protection.

Furthermore, as regards the methods of PGD, the ethical discussion with respect to the application of extracorporeal fertilisation techniques as a prerequisite for PGD is cast in a new light. Critics assert that their admissibility used to be bound to other prerequisites and objectives. In the context of their application for PGD however, they are used for couples that are also able to give birth to children without the methods of assisted reproduction. This means that the scope of application of these techniques is changing. Whereas in the original field of application the establishment of a pregnancy and thus ultimately the birth of a child is the objective, in the context of PGD they are used to select embryos with specific diagnostic findings. Thus, selection becomes the prime objective, while pregnancy and the birth of a child who shall not bear a certain characteristic come only second.

With the PGD several objectives of the application are pursued. The ethical debate centres on the question whether, and if so to what extent, these objectives justify possible violations of the embryo’s right to protection. A current objective of the application is the increase in the chances of having offspring without the risk of passing on genetic diseases. In this context for example a case from the UK is discussed in which a couple received PGD in order to prevent passing on a genetic form of breast cancer. In an ethical perspective in terms of the objective of the application discussions are going on especially about the difficulty of choosing the diseases or characteristics that ought to be diagnosed respectively the characteristics or criteria of selection (fatal diseases, late-onset diseases, untreatable diseases etc.). 

Another objective of the application of PGD is the production of so-called saviour siblings. They are children with respect to their suitability as a tissue donor to help out an older sibling for their treatment. For this purpose the embryo with the highest genetic congruence with the ill child gets implanted after an in vitro fertilisation via PGD. After giving birth the stem cells of the cord blood or the bone marrow of the new born shall help the ill sibling. Supporters of this field of application assert that, in such a case, PGD allows to help a child affected with a life-threatening disease, for whom no other compatible donor can be found. Critics object to this that an embryo is not created primarily for its own sake, but with the aim of helping another human being, this leading to complete instrumentalisation which cannot be ethically justified. Moreover, and especially with regard to further treatments, this gives rise to the question of whether a child who is brought into the world for this purpose would have the opportunity to make a decision of his or her own free will in favour of or against helping the sibling and possibly suffering the pain involved. What is more, a considerable number of healthy embryos is generated and rejected again. 

In the context of this discussion, it is of substantial importance whether there are no other possibilities of treatment that might be successfully applied, whether a fatal disease is to be treated and whether the child born after PGD will possibly have to repeatedly undergo painful operations. A third objective of the application concerns about the selection of embryos for non-disease-related characteristics which are rejected as ethically problematic, e.g. the embryo’s sex. However, supporters of this possible application of PGD argue that also social criteria should be admissible. Especially with regard to non-disease-relevant characteristics, PGD has raised fears of a slippery slope to eugenic selection and ethically disputed research on embryos.

The consequences of authorising PGD, i.e. social consequences as well as consequences for disabled and non-disabled individuals, are also often discussed: with regard to social consequences, there are fears of an increasing discrimination against sick and disabled persons. If the methods of PGD were authorised, couples who wish to have a child could be subject to social pressure to prevent disabled life, suggesting that parents of potentially disabled children should use the methods of PGD for the common good and in order to avoid higher costs related to care and assistance for a disabled or sick child to society. The mechanisms that could result from this would not increase reproductive freedom which is often cited in the context of PGD, but, on the contrary, make it more difficult. Some say, this has already become visible in the example of PND: the availability of the methods alone leads to social pressure to use them as well. Critics also assert that an authorisation of PGD would result in "unworthy of life"-judgements being approved. This would have a serious impact, especially on the life situation of disabled and sick persons. In the case of PGD being authorised, they would be confronted with an officially tolerated "unworthy of life"-judgement which would radically question their own existence.

Other areas of discussion concern questions that deal with the autonomy of the couple, the role and the concept of woman, the doctor-patient relationship (in this respect, the couple, the woman and/or the embryos are considered as patients) and adequate advice and assistance for the couple, for the woman in particular, but also for the health personnel.

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