Preimplantation Genetic Testing for More Than One Genetic Condition

Clinical and Ethical Considerations and Dilemmas

V. van der Schoot; W. Dondorp; J.C.F.M Dreesen; E. Coonen; A.D.C Paulussen; G. deWert; C.E.M. de Die-Smulders

Disclosures

Hum Reprod. 2019;34(6):1146-1154. 

In This Article

Discussion

Clinical Feasibility

We report 40 applications for cPGT-M/SR. Sixteen couples started their treatment. Thirty-nine IVF cycles led to the analysis of 187 embryos and 28 embryo transfers, resulting in five healthy children. Pregnancy rate per transfer was 21%. This is in line with the figure reported by the PGT-consortium (Harper et al., 2012). In half of the started cycles, we could at least identify one embryo suitable for transfer. Our results clearly demonstrate the feasibility of cPGT-M/SR.

Bearing these results in mind, we expect an even better outcome after full implementation of comprehensive methods as SNP or NGS-based haplotyping that allow simultaneous testing for an unlimited number of genetic disorders hence avoiding multiple biopsies.

Scope for Wider Indications Setting

In the experience of our centre with cPGT-M/SR, a large percentage of couples distinguished between a primary and secondary condition in terms of perceived relative seriousness. However, no cases were listed where the secondary condition would not on its own have met the 'high risk of a serious condition' standard. The lack of requests for cPGT involving a mild condition as secondary to an accepted PGT-M/SR condition is not surprising, given that the Dutch 'PGD regulations' strictly adhere to the 'high risk of a serious condition' standard and do not recognize—or even discuss—the case for making an exception for applications with an altered proportionality profile (Tweede Kamer der Staten Generaal, 2009). If ESHRE's reasoning on this point is sound, as we think it is, this may have as a consequence that in the Netherlands and other countries that also fail to allow for this exception, some are denied without a good reason what might have been a meaningful option for them. However, an important qualification is that the reasoning behind accepting a lower standard is only valid as long as a further hormone stimulation cycle would not be needed in order to successfully complete a cPGT procedure. While trying a further cycle may be necessary to obtain transferable embryos not also affected by the secondary target condition, this inevitably comes with the full array of burdens, risks and (moral) costs of regular PGT-M/SR. For this to be acceptable in terms of the 'high risk of a serious disorder' standard, the secondary condition would have to be sufficiently high risk and serious to qualify as a PGT indication on its own (Dondorp and De Wert 2019). Clearly, in countries upholding this standard, making exceptions for cPGT cases requires adequately informing the applicants about this qualification as part of pre-test counselling.

Requests for Transferring Affected Embryos: Three Categories

There are three types of situation in which professionals may be confronted with requests to transfer affected last chance embryos in cPGT-M/SR (Dondorp and De Wert 2019). At one end of the spectrum, one may think of cases where, notwithstanding a possible categorization by the applicants in terms of primary and secondary, both conditions are evidently highly serious. In our view, transferring embryos leading to disorders in this category would be difficult to reconcile with the responsibility of professionals to take account of the welfare of the child-to-be. Using an example from the list of cPGT-M/SR cases in our centre (Table I), a potential request by couple #25 to transfer any last chance embryos that would lead to a child with either ataxia with oculomotor apraxia type 1 (AOA1) or spinal muscular atrophy type 1 (SMA1) should be rejected. This scenario is theoretical in so far as couples are not likely to ask for the transfer of affected embryos in such cases.

At the opposite end are cases where the secondary condition is clearly not 'high risk and serious', whereas the primary condition is. If, following the reasoning by ESHRE, cPGT-M/SR is allowed for such cases, this may lead to requests for transferring affected last chance embryos that professionals have no good reason to reject, given that such a transfer would not involve a high risk of a child with a seriously diminished quality of life. Here again, CCD might be an example of such a secondary condition. In such cases, a problem would rather arise with couples requesting an additional hormone stimulation cycle as a further attempt to obtain transferrable embryos not affected by the secondary condition. As explained in the previous section, such a further attempt would bring the proportionality balance back into to the range where the 'high risk of a serious condition' standard would seem to exclude conditions such as CCD.

Probably the most difficult cases fall in the middle of the spectrum. These comprise requests for transferring last chance embryos where the secondary condition, although an accepted indication, is in the grey area where it can be a matter of debate if the condition qualifies as 'high risk and serious'. As an example, one may think here of BRCA-mutations in female fetuses. As these conditions have been subject to quite some discussion about whether they would qualify as acceptable indications under the 'high risk of a serious condition' standard, it is not obvious what the response should be with regard to requests for transferring 'last chance' embryos affected with one of those conditions (Dondorp and De Wert, 2019). We propose shared decision-making about such 'grey area' cases, in which the particular views of the applicants and the history and context of their experiences with the condition ('the story behind the request'; Soto Lafontaine et al. 2018) are taken into account. The one case (couple #14) where last chance embryos affected with Peutz–Jeghers syndrome were transferred on request from a couple having cPGT-M, can perhaps be argued to fall in this middle category.

Scope for Reverting to Single Condition PGT-M/SR

Our conclusion with regard to the first type of cases entails that the couple may end up empty-handed. A possible way out in these cases is to go ahead with a new cycle for one condition only (the condition regarded as primary by the couple). While this would involve a 25–50% chance of embryos with the secondary condition being transferred (in monogenic disorders), professionals (and couples) may feel more comfortable with this alternative as compared with transferring embryos known to be affected. However, in cases with two fully penetrant conditions that are both in the higher range of seriousness, it can be questioned whether testing for just one of those conditions is ethically acceptable, given that a 25 or 50% transmission risk would still amount to a high risk of a child with a seriously diminished quality of life. Ethically, this is similar to doing 'just IVF' when an infertile couple is known to be at a high risk of having a child with a serious disorder (Dondorp and De Wert, 2019). Some centres may find this acceptable on the condition of a clearly indicated intention on the part of the couple to make use of PNT and ask for a termination in case the fetus turns out to be affected (De Wert et al., 2014). Of course, any such understandings about further reproductive decision-making are a matter of trust that cannot be enforced. However, they do relieve professionals from a co-responsibility for the welfare of a seriously affected child that might be born as a result of the couple's backtracking on what was agreed at the pre-treatment stage (Pennings et al., 2003). In cases where the secondary condition is more in a grey-area of risk and seriousness, reverting to PGT-M/SR for the primary condition only may well be acceptable. But if so, solving the dilemma through transferring embryos affected with that grey-area condition, if that is the couple's request, should perhaps be regarded as acceptable as well, also because that would avoid a further cycle with its burdens and costs. It is important that centre-policies with regard to such choices are clearly defined and timely discussed with the couple.

Timely Information and Counselling

Our data and our analysis underscore the importance of timely information and counselling regarding all relevant aspects of cPGT-M/SR. This includes the inevitably lower number of embryos suitable for transfer, also in the light of other risk factors reducing success rate, such as maternal age. Other options than cPGT-M/SR for both conditions may need to be considered. In addition to the possibility of PGT for one condition and offering PNT for the other, the use of donor gametes to exclude the genetic burden in one of the parents may be an acceptable option for the couple. Moreover, the applicants should be informed already at the pre-test stage of centre policies with regard to the ethically laden choices that may emerge in the process of cPGT-M/SR. This should also include information about the scope for allowing the applicants a change of mind during later stages of the procedure. The one case in our centre where affected embryos were eventually transferred (couple #14), involved strained decision-making at a later stage where professionals had wrongly assumed that there was a clear understanding with the couple that they did not want embryos with either condition to be transferred.

Concluding Remarks and Recommendations

  1. cPGT-M/SR is feasible.

  2. cPGT-M/SR should be discussed as a possible treatment option with couples at high risk for offspring with more than one genetic condition.

  3. Couples applying for cPGT-M/SR should be informed at the stage of pre-treatment informed consent that this procedure entails a lower chance of success than PGT for one condition, and an even further decrease of chances of pregnancy. Pre-test counselling should include a discussion of the couple's views with regard to the relative importance of preventing the birth of a child with either condition. Do they think of those conditions in terms of primary and secondary?

  4. In countries where PGT-M/SR is only allowed for couples at a high risk of transmitting a serious disorder, this currently limits the scope for the conditions that can be accepted as a secondary condition. However, to the extent that cPGT-M/SR involves an altered proportionality balance, a case can be made for allowing secondary conditions of lower risk and seriousness also in those countries.

  5. Centres allowing cPGT-M/SR may be confronted with requests for transferring embryos affected with what the couple regards as the secondary condition. It is important to have a proactive discussion of all possible outcomes already at the stage of pre-treatment informed consent. This discussion should include the policy of the centre with regard to dealing with such transfer requests. This may lead to a couple-specific proposal for ranking embryos for transfer that takes account of the couple's preferences as well as of the limits to acceptable transfers set by the centre. As we have discussed, professionals should not go ahead with requests for transferring an embryo where there is a high chance of this leading to a child with a seriously diminished quality of life.

  6. Couples may change their minds with regard to the priority of their preferences during the cPGT-M/SR procedure. A patient-centred policy would require professionals to allow for this as much as reasonably possible, while clearly explaining the inevitable limits to this.

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