IVF-related research

With this report (the last in a series of three) the IVF Committee of the Health Council concludes its response to the request for an advisory report submitted in 1994. The report indicates the current level of knowledge with regard to pre-implantation genetic diagnosis (PGD) and describes current developments in the field of research concerned with improving IVF. A separate chapter is devoted to the issue of whether it is permissible to use human embryos for research aimed at further developing PGD or improving IVF. It also explores the conditions to be imposed on such research. Finally, the Committee reviews its previous reports, in terms of the extent to which the introduction of artifïcial reproduction technology in the Netherlands has been judiciously implemented.

Pre-implantation genetic diagnosis

Pre-implantation genetic diagnosis (abbreviated to PGD) is a method which combines genetic diagnosis and artifïcial reproduction techniques. In PGD, diagnosis to detect monogenic or chromosome abnormalities is carried out on the oocyte or on the embryo, in vitro. There are three variants: polar body biopsy (diagnosis using the oocyte), blastomere biopsy (diagnosis using the embryo, during cleavage) and trophoblast biopsy (diagnosis using the embryo at the blastocyst stage). PGD is carried out in conjunction with an IVF treatment or ICSI treatment. Depending on the result of the test, a decision can be taken to refrain from fertilization of the oocyte or from transfer of the embryo to the womb. This technology allows the woman in question to avoid the risk of bearing a child with a given abnormality.

The polar body and blastomere biopsy forms of PGD have already been in use for about 10 years, in the context of clinical research. In the Netherlands, the University Hospital of Maastricht has been involved in this research for several years. To date, more than 100 children are born following PGD, two of them in the Netherlands.

The aim in developing PGD was to create an alternative to existing methods of prenatal diagnosis (chorionic villus sampling and amniocentesis). The scope of this technique was, initially, restricted to fertile couples with an individually elevated chance of a monogenic (possibly sex-linked) or chromosomal abnormality in their offspring. Currently, throughout the world, more than half of the cases in which PGD is used involve subfertile couples undergoing an IVF treatment who, as a consequence of the woman’s age, have an elevated chance of conceiving a child with a chromosomal abnormality. This involves the routine use of PGD, also referred to as pre-implantation genetic screening (PGS).

The various forms of PGD are still in the stage of scientific research. There is still much uncertainty about various aspects of the method, particularly the reliability of the diagnosis and its safety for the offspring involved. Further research is required in this area, along with studies to determine how PGD influences an embryo’s chance of implantation and the chance of an ongoing pregnancy.

The committee gives special attention to the acceptability of various forms of biopsy. It has been suggested that blastomere biopsy is equivalent to the creation of embryos for research purposes. This depends on whether, at the stage the biopsy is taken, the embryo cells can individually develop into a complete new organism. Based on the scientific literature currently available, the committee concludes that this is most likely not so.

Another ethical dilemma is the selection of embryos after PGD. Unavoidably, the question of the acceptability of taking carrier status of recessive genetic diseases as a criterion for selection comes to the forefront.

Finally, the Committee addresses the applicable legislation and regulations such as the Medical Research Involving Human Subjects Act and the Special Medical Treatments Act.

Research aimed at improving IVF

Only 15 to 20% of all initiated IVF treatment cycles lead to an ongoing pregnancy. Any increase in this chance is of enormous significance to those couples suffering from involuntary childlessness who must resort to IVF. Fewer couples will be disappointed. Women will less often have to undergo hormone stimulation and follicle puncture, thereby reducing their exposure to the risks and distress associated with these procedures. In this connection, the Committee addresses itself to research aimed at improving the various aspects of the laboratory phase of IVF, including culture conditions.

Alleviation of the distress and risks endured by the woman can also be expected of research aimed at improvement of protocols for hormone stimulation. It would be even better if hormone stimulation could be omitted entirely. Accordingly, the Committee emphasizes the importance of further research into the possibility of culturing immature oocytes outside the woman’s body until they are mature enough to be fertilized. This procedure is called in vitro maturation of oocytes (IVM). Research in this area has been going on for quite some time. Although children have been born after IVM, there is no immediate prospect of its introduction into IVF practice. The results obtained to date have been disappointing. In addition, there is apprehension that IVM may involve certain health risks to the offspring. The Committee believes that no further clinical research should take place until these issues have been resolved.

Similar reasoning applies to research into the possibility of keeping oocytes in frozen storage for later use (cryopreservation of oocytes). This line of research has also met with very little success. Furthermore, the technique has been introduced into clinical use before its safety has been adequately investigated in animal experiments. However, the Committee does emphasize the potential significance of this research. Should it become possible to hold oocytes in frozen storage for later use, then it will no longer be necessary to fertilize all oocytes derived by hormone stimulation. This could, to a large extent, prevent the creation of surplus embryos. The Committee considers this to be a moral gain. In addition, cryopreservation of oocytes could be important for women who are at risk of becoming prematurely infertile as a result of treatment for cancer etc. They could have their oocytes frozen to ensure that they would have the option of bearing children at a later date (fertility insurance).

New methods and techniques in the field of artificial reproduction are sometimes tested in humans without adequate preclinical research in animals (for possible harmful effects, including longer term effects and effects spanning several generations). Any possible safety hazards are thus shifted to the woman and to the child. The Committee considers this to be unacceptable. Finally, the Committee points out that preclinical research using human embryos can often contribute to a further reduction of the uncertainties left by animal experiments regarding the prudence of progressing to clinical application.

Research using human embryos

In a separate chapter, the Committee gives a comprehensive description of the discussion surrounding the ethical and legal acceptability of research using human embryos. It also sets out its own position. With reference to previous advice from the Health Council, the Committee states that while a given value should be assigned to the embryo in vitro (by virtue of which it deserves respect), this value is relative and can be overridden when other, more imperative interests are involved. Also, the Committee does not consider the creation of embryos specifically for research to be unacceptable a priori, although the use of surplus embryos is to be preferred on moral grounds. The Committee considers it acceptable for embryos to be created for research purposes only when such research cannot be carried out using surplus embryos (either because of the nature of the research or because no surplus embryos are available). The requisite oocytes should be obtained in a morally sound manner.

The Committee takes the view that both the further development of PGD and the improvement of IVF treatment are of such importance to human health that, in this context, it can be acceptable to perform research on human embryos. This does not automatically mean that a concrete research proposal would be acceptable. This depends on whether the research can be expected to produce information which is relevant to these objectives and which cannot be obtained by other means. In addition, it must also satisfy the other conditions applicable to research involving human embryos. This would be judged, on a case by case basis, by the Central Committee to be set up in accordance with the provisions of the Medical Research Involving Human Subjects Act.

In certain cases, dependent on the nature of any uncertainty remaining after the completion of animal experiments and on the severity of the possible consequences, the Committee would consider unacceptable researchers refraining from preclinical embryo research or not awaiting the results of such research and proceeding directly to the clinical application of a given method or technique. Here it makes no decisive difference whether the research in question uses surplus embryos or whether it requires the specific creation of human embryos. Under no circumstances whatsoever may women and children be turned into trial subjects for the sake of protecting embryos.

Evaluation

Finally, the Committee has considered whether artificial-reproduction technology has been introduced in the Netherlands along the lines of the principle of ’evidence-based medicine’. In this evaluation, the Committee refers to analyses and conclusions from its previous reports on ICSI and IVF. It postulates a reference model for the introduction of’special’ medical technology. The Committee concludes that this introduction has not in each case proceeded entirely satisfactorily. Steps in the requisite research have been omitted. With regard to the future, the solution should involve setting priorities for research. This area is the common responsibility of government, health professionals and financiers.

Recommendations

Regarding PGD:

• For the time being, the use of PGD requires a research protocol.
Concrete proposals for preclinical or clinical research in this field require
evaluation by the Central Committee to be set up in accordance with the
provisions of the Medical Research Involving Human Subjects Act.
The Clinical Genetics Planning Decree should be declared to be applicable to the
DNA research carried out within the framework of PGD.
Clinical research should take place in centres where sufficient expertise is
available in the fields of reproduction, embryology and genetics. These centres
must possess a permit based on the IVF Planning Decree. Stringent requirements
must be imposed on patient information and supervision.
• When formulating proposals for studies in the field of PGD, the inclusion and exclusion criteria need be no stricter than those used for prenatal diagnosis (with the exception of screening for risks related to advanced maternal age).
• If it is to be routinely offered to IVF couples, there must be more clarity about whether PGD should be regarded as population screening requiring a permit within the framework of the Population Screening Act.
Long-term follow-up of children born through the use of PGD is required. The Committee considers it important that Dutch researchers affiliate themselves with the existing international registration of study results (as the Maastricht group has already done). This registration should be so organized that the collected data can be released for further analysis, with a view to the necessary follow-up etc.

With regard to research involving human embryos:

• In the announced law on procedures involving human gametes and embryos, it must be stipulated that proposals for research using human embryos in vitro require approval by the Central Committee to be set up in accordance with the provisions of the Medical Research Involving Human Subjects Act.
• Such research must, in any event, meet the following criteria:

• it involves a major health issue;
• the research proposal is scientifically sound;
• the data required cannot be obtained in any other way;
• the research does not use any more embryos than are strictly necessary;
• no embryos are created for research which can also be carried out using surplus embryos
• the informed consent is obtained of those authorized to determine the fate of the embryos or (if the research implies the creation of embryos) gametes;
• the interests of oocyte-donor candidates are protected (in case of research for which embryos are created)
• embryos used for research purposes may not subsequently be transferred to the
womb.

The new legislation relating to human embryos and gametes should not contain a ban on the creation of embryos for research purposes. Ratification by the Netherlands of the Treaty on Human Rights and Biomedicine of the Council of Europe should be made subject to a proviso on this point.