, London, UK.
J Assist Reprod Genet. 2021 Aug;38(8):1971-1978. doi: 10.1007/s10815-021-02174-5. Epub 2021 Mar 27.
The objective of this virtual study was to simulate a full cycle and assess the costs and benefits to a couple with a reciprocal translocation, using current techniques for preimplantation genetic testing and comparing reporting every chromosome with only reporting those involved in the rearrangement.
A simulation was constructed for women under the age of 35 years, where vitrified-warmed embryos were transferred one at a time in a first full cycle following preimplantation genetic testing using next-generation sequencing and sampling the trophectoderm at the blastocyst stage. The effect on pregnancy outcomes (live birth, clinical miscarriage and biochemical pregnancy) was evaluated for different reporting strategies for embryo transfer to (i) report only the rearranged chromosomes and transfer embryos with a normal or balanced test result for the translocation (targeted), or (ii) report every chromosome and exclude from transfer all embryos with an abnormal test result (exclusion), or (iii) exclude only those consistent with an unbalanced translocation and/or unrelated non-mosaic whole-chromosome aneuploidy and assign those with samples consistent with a normal or balanced translocation complement and unrelated mosaic aneuploidy or segmental imbalance (embryos of uncertain reproductive potential) a lower transfer priority (ranking). The number of individual women whom might benefit by avoiding an adverse pregnancy outcome (biochemical pregnancy, clinical miscarriage) or be disadvantaged by not achieving a live birth was evaluated. The financial cost of the different reporting strategies and the time taken to complete a cycle were also considered.
The simulation showed that compared to only reporting the translocation chromosomes (targeted reporting), testing every chromosome and ranking embryos by test result for transfer was a cost-effective strategy to avoid an adverse pregnancy without compromising the chance of a live birth. Excluding from transfer embryos with a test result consistent with a normal or balanced translocation complement of uncertain reproductive potential was an inferior strategy because it resulted in fewer live births from a full cycle. Reporting only the translocation chromosomes was an inferior strategy because it was less effective than ranked reporting of every chromosome to avoid an adverse pregnancy. Compared to targeted reporting, the ranked and exclusion strategies marginally reduced the overall cost and time taken to complete a full cycle. The ranking strategy avoided 1 adverse pregnancy for 12 cycles started, compared to 1 in 10 for the exclusion strategy which also resulted in 1 in 22 fewer women achieving a live birth. A minority (< 10%) of couples benefited by avoiding at least 1 adverse pregnancy whilst also reducing the time and cost for a complete cycle; most (> 70% ) couples received no benefit additional to targeted reporting and had the same outcome for pregnancy, time and cost.
The primary objective of PGT-SR for couples with a reciprocal translocation is to avoid a pregnancy with a chromosomally unbalanced product of the translocation and to reduce the risk of miscarriage, at least to that expected for couples with normal karyotypes. Trophectoderm sampling at the blastocyst stage with testing using NGS is an effective approach; however, ranking and excluding from transfer embryos with abnormal test results for unrelated chromosomes is problematical and is likely to be detrimental to achieving a live birth. Targeted reporting, where only the results of the chromosomes involved in the translocation are known, should be preferred to achieve a live birth. A best effort should be made to follow up and investigate all pregnancies following PGT-SR. Once the reproductive outcome is known (biochemical pregnancy, clinical pregnancy, live birth), the chromosomes unrelated to the rearrangement can be analysed as an experimental study. The risk/benefit of avoiding an adverse pregnancy vs reducing the chance of a healthy delivery should be a decision for each individual couple and informed by appropriate genetic counselling for their specific translocation and history.
本虚拟研究旨在模拟一个完整周期，并评估对于具有相互易位的夫妇使用当前的胚胎植入前遗传学检测技术进行检测的成本和收益，并比较报告所有染色体与仅报告易位涉及的染色体的情况。
为年龄在 35 岁以下的女性构建了一个模拟，在使用下一代测序进行胚胎植入前遗传学检测后的第一个完整周期中，一次转移一个经玻璃化冷冻-解冻的胚胎，并在囊胚阶段取滋养外胚层进行采样。不同的胚胎转移报告策略对妊娠结局（活产、临床流产和生化妊娠）的影响进行了评估：（i）仅报告易位染色体，并转移具有正常或平衡易位检测结果的胚胎（靶向）；（ii）报告所有染色体，并排除所有具有异常检测结果的胚胎（排除）；（iii）仅排除那些与不平衡易位一致的胚胎和/或与非整倍体无关的整体染色体非整倍体，并对那些与正常或平衡易位互补和与非整倍体无关的镶嵌体或片段失衡一致的样本（具有不确定生殖潜力的胚胎）给予较低的转移优先级（排名）。评估了避免不良妊娠结局（生化妊娠、临床流产）或因未获得活产而处于不利地位的个别女性的数量。还考虑了不同报告策略的财务成本和完成周期所需的时间。
模拟表明，与仅报告易位染色体（靶向报告）相比，测试所有染色体并根据转移的测试结果对胚胎进行排名是一种避免不良妊娠而不影响活产机会的具有成本效益的策略。排除具有不确定生殖潜力的正常或平衡易位互补测试结果的胚胎是一种较差的策略，因为它会导致从完整周期中获得的活产减少。仅报告易位染色体是一种较差的策略，因为它不如按排名报告所有染色体有效，以避免不良妊娠。与靶向报告相比，排名和排除策略略微降低了完成完整周期的总成本和时间。排名策略避免了 12 个开始的周期中的 1 次不良妊娠，而排除策略则避免了 1 次，同时也导致了 1 次活产减少了 22 次。少数（<10%）夫妇通过避免至少 1 次不良妊娠，同时减少完整周期的时间和成本而受益；大多数（>70%）夫妇除了靶向报告外没有获得额外的益处，并且在妊娠、时间和成本方面的结果相同。
对于具有相互易位的夫妇，PGT-SR 的主要目的是避免染色体不平衡的易位产物妊娠，并降低流产风险，至少降低与正常核型夫妇相同的风险。囊胚阶段的滋养外胚层取样和使用 NGS 进行检测是一种有效的方法；然而，对与易位无关的染色体进行异常测试结果的胚胎进行排名和排除是有问题的，并且可能对实现活产不利。与实现活产相比，应该优先选择靶向报告，即仅报告易位染色体的结果。应该尽力跟进和调查所有 PGT-SR 后的妊娠。一旦获得生殖结局（生化妊娠、临床妊娠、活产），就可以作为一项实验研究分析与重排无关的染色体。避免不良妊娠与降低健康分娩机会的风险/收益应该是每个夫妇的决定，并由对他们特定的易位和病史进行适当的遗传咨询来告知。
