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

Results

In this section, we present both our clinical data and the findings of our ethical exploration with regard to how cPGT/M-SR relates to criteria for indications-setting and transfer-decisions.

Clinical Data

Applications and counseling. We reviewed requests for cPGT-M/SR from 40 couples (Table I). These involved either two structural chromosomal anomalies (n = 10), two monogenic disorders (n = 7), or combinations of both (also including mitochondrial diseases) (n = 23). Three out of four couples applying for cPGT for two autosomal recessive diseases were consanguineous.

When asked, eighteen couples (45%) identified a 'primary' and 'secondary' condition in terms of perceived severity. Neurofibromatosis type 1 (NF1) was perceived as the primary condition for all three couples requesting cPGT for NF1. HBOC was perceived as the secondary indication for five out of seven couples asking for cPGT. CF was perceived as the secondary condition in three out of four requests involving this disease. Twenty-two couples (55%) perceived both conditions for which they requested cPGT as equally severe or could not make a differentiation because of the nature of the disorders (for example two structural chromosomal anomalies, both with a high risk of miscarriage) (Table I).

Twenty-one couples (52%) proceeded with cPGT treatment. Combinations of disorders comprised two chromosomal abnormalities (n = 6), monogenic disorders (n = 8), or a combination of the above and mitochondrial diseases (n = 7). Five of these couples are still awaiting protocol development. Nineteen couples (48%) refrained after intake. Reasons to refrain were low chance of success (n = 4), opting for PGT for one disorder (n = 3), preference for prenatal testing (PNT) (n = 3), medical contra-indication for IVF-treatment (n = 2), ending of the relationship (n = 2), PGT-treatment in a hospital abroad (n = 2), treatment not possible because of technical reasons (n = 1), religion (n = 1), and spontaneous pregnancy (n = 1).

cPGT-M/SR treatments. For 16 couples, treatment protocols were developed; six for combinations of chromosomal anomalies by either FISH or array comparative genomic hybridization (CGH) analysis, seven for two monogenic disorders by marker and/or mutation analysis, two for a monogenic and a mitochondrial disorder by quantative analysis and one for a combination of a monogenic disorder and a chromosomal anomaly (Table II). All treatment protocols were based on blastomere biopsies (Day 3).

The 16 couples underwent 39 cycles and 187 embryos were analyzed (Figure 1). Of these, 47 (47/187 = 25%) displayed the wild-type or normal/balanced genotype of both tested disorders and thus were genetically suitable for transfer. These concerned 15 out of 52 embryos analyzed for two autosomal dominant disorders (15/52=29%), 9 embryos out of 17 tested for two autosomal recessive disorders (9/17 = 53%), 10 embryos of 77 analyzed for two chromosomal anomalies (10/77 = 13%) and 13 of the 23 embryos analyzed for other combinations than mentioned above (13/23 = 57%). Of the other 140 analyzed embryos, 46 were free from both conditions tested for and 59 embryos were affected by both. Of 35 embryos no conclusive results could be obtained.

Figure 1.

Outcome embryo analysis in cPGT-M/SR (n=187). Number of embryos (% of total in category) not affected for both conditions (lighter shade - top) and affected for one or both conditions (darker shade - bottom), for two autosomal dominant conditions (column 1), autosomal recessive conditions (column 2), chromosomal anomalies (column 3), other combinations of conditions (column 4), and the total of embryos analyzed (column 5).

Thirteen couples underwent one or more embryo transfer(s). A fresh embryo transfer was performed in 21/39 (54%) of the cPGT cycles. An additional seven frozen embryo transfers were performed, adding up to a total of 28 transfers (28/39 cycles = 72%). Three double embryo transfers were performed (3/28 = 11%). In three consecutive PGT cycles of couple no. 14, no embryos free from both disorders were available. Although in the counselling before treatment, they clearly stated that they opted for exclusion of both disorders, the couple requested transfer of an embryo affected with Peutz–Jeghers syndrome in all three cycles. No pregnancy was achieved.

Six single embryo transfers (four fresh and two frozen) resulted in a positive HCG test (6/28 = 21%). In four of these cases, two blastomeres were biopsied (Table II). One pregnancy ended in a miscarriage at 6+4 weeks gestational age, genotype unknown. Five children were born, three boys (Table II no. 1, 9, 20) and two girls (Table II no. 9, 37). Prenatal or postnatal testing to confirm cPGT diagnosis was performed for two couples (no. 9 and no. 37). In both cases, the cPGT results were confirmed. Couple 9 obtained two healthy PGT children, one from a fresh transfer and the second resulting from a frozen cycle.

Couple no. 10 requested analysis for only the MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) mutation after two unsuccessful PGT treatments for both the MELAS and the BRCA2 mutation. This third cycle resulted in an ongoingbpregnancy.

Ethical Exploration

Indications setting for cPGT-M/SR. In countries where PGT-M/SR is available, its lawful application is often limited to couples with a 'significant' or 'high' risk of transmitting a 'serious' genetic disorder to their offspring (see Figure 2). In this paper, we will refer to this as 'the high risk of a serious disorder' standard. The reasoning behind this requirement often remains unspecified. However, ESHRE's Task Force Ethics & Law has suggested that the standard should be understood as reflecting the 'proportionality' of PGT-M/SR (De Wert et al., 2014). This notion refers to the balance between the benefits that PGT may have for the applicants on the one hand and the various aspects that make it a morally sensitive technology on the other. If this interpretation is correct, then a significant change on the 'issues and concerns' side of the proportionality balance may lead to a different range of acceptable indications (De Wert et al., 2014). As argued by the Task Force, there are two situations where this would apply. One is PGT-M/SR for applicants with a fertility problem that gives them a separate indication for IVF or intracytoplasmatic sperm injection (ICSI). The second is where people have an indication for PGT-M/SR and want to add testing for a further disorder for which they are also at risk. In both situations, a significant part of the burdens and (moral) costs have already been taken account of, either with respect to IVF or ICSI as fertility treatment, or for doing PGT for the primary disorder. Adding PGT-M/SR to fertility treatment or doing PGT-M/SR for a further condition could therefore be considered also for lower risk or less serious conditions. As we have suggested elsewhere (Dondorp and De Wert, 2019), a possible example is cleidocranial dysostosis (CCD), an autosomal dominant skeletal spectrum disorder involving bone deformities (collarbone, skull) and abnormal teeth (Machol et al., 2017). While this disorder comes with a high penetrance, the clinical features are relatively mild. As CCD only moderately affects the quality of life in most patients, it seems that a 'stand alone' PGT-M procedure for this disorder would be at odds with the 'high risk of a serious disorder' standard. However, should the applicants have an indication for IVF or ICSI as fertility treatment, or if they are already having PGT for an accepted (M/SR) indication, holding on to that same standard would seem too strict.

Figure 2.

Legislation limiting the scope of acceptable PGT-M/SR indications.

Transfer decisions after cPGT-M/SR. According to a classical rule of PGT-practice, 'affected embryos' (meaning, embryos with the very mutation or abnormality targeted in PGT-M/SR), should not be transferred to the womb (Thornhill et al., 2005). An important argument for this is that in medically assisted reproduction, professionals should take account of the welfare of the child that they are causally involved in creating (Pennings et al., 2007). As pointed out by ESHRE, there is a broad international consensus that requests for reproductive assistance should not be granted if chances are high that the resulting child will have a seriously diminished quality of life. However, for this to lead to the 'do-not-transfer' rule, it must be the case that PGT-M/SR is only done for conditions that clearly fall in the range of 'high risk and serious'. Given that in the past decennium, the scope of accepted indications has widened beyond the limited range of classical disorders to also include conditions marked by a less than complete penetrance, a later time of onset, and at least some treatment or surveillance options (e.g. hereditary breast and ovary cancer (HBOC) or hypertrophic cardiomyopathy), it has become less obvious that the 'do-not-transfer' rule would not allow for exceptions. In a recent focus group study about professional views about these issues, some participants said requests for transferring affected embryos were difficult to swallow. In their view, such requests signalled a capricious attitude on the part of the couple, out of tune with professional efforts to help them avoid the reproductive risk for which they had PGT in the first place. However, others regarded such requests more favorably as an understandable adjustment of priorities in the light of a reassessment of what is realistically feasible (Soto Lafontaine et al., 2018). This, they said, was especially understandable in cases where no further hormone stimulation cycles were realistically possible and where, because of their fertility problem, the alternative option of natural reproduction was not available to the couple. When in such cases the only otherwise good quality embryos available happen to be affected, these represent the couple's last chance to have a genetically related child. In the UK, regulations allow considering such last chance affected embryos for transfer at the patients request, but permission is required from a clinical ethics committee on a case-by-case basis (Human Fertilisation & Embryology Authority, 2019). This has been done for example for BRCA1 carrier embryos.

Assuming, for the sake of debate, that cPGT-M/SR is offered to couples that are normally fertile, it would seem that talk of 'last chance embryos' does not apply. However, this impression is mistaken, especially with regard to those couples who distinguish between a primary and a secondary condition in terms of perceived severity. Faced with the message that no embryos free of either condition are found, then in cases where trying a further hormone-stimulation cycle is not an option, they may request the transfer of embryos affected by what in their view is the secondary target condition. These are 'last chance embryos' in the wider sense of enabling the couple to start a pregnancy with the confidence that the resulting child will not be affected by the disorder that they want to avoid most. Clearly, making this request entails accepting that the child has a high chance of developing the secondary condition, the one that they had preferred to be able to avoid as well, albeit with a lower priority. Allowing cPGT-M/SR may thus lead to an increased number of requests for transferring affected embryos.

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