目的:这项虚拟研究的目的是模拟一个完整的周期,并评估一对相互易位的夫妇的成本和收益,使用当前的技术进行植入前遗传检测,并将报告每条染色体与仅报告涉及重排的染色体进行比较。
方法:对35岁以下的女性进行了模拟,在使用下一代测序并在胚泡阶段对滋养外胚层进行采样的植入前遗传学测试后,在第一个完整周期中一次移植一个玻璃化的温热胚胎。对妊娠结局的影响(活产,临床流产和生化妊娠)对胚胎移植的不同报告策略进行了评估,以(i)仅报告重排的染色体和具有正常或平衡的易位测试结果的移植胚胎(目标),或(ii)报告每条染色体,并排除所有测试结果异常的胚胎(排除),或(iii)仅排除那些与不平衡易位和/或无关的非马赛克全染色体非整倍性一致的人,并将那些与正常或平衡的易位互补和无关的马赛克非整倍性或节段性不平衡(不确定生殖潜力的胚胎)的样本分配给较低的转移优先级(排名)。通过避免不良妊娠结局(生化妊娠,临床流产)或因未实现活产而处于不利地位的评估。还考虑了不同报告策略的财务成本和完成一个周期所需的时间。
结果:模拟表明,与仅报告易位染色体(有针对性的报告)相比,测试每个染色体并根据测试结果对胚胎进行转移排序是一种具有成本效益的策略,可以避免不良妊娠,而不会影响活产的机会。排除具有正常或平衡的易位补充的测试结果与不确定的生殖潜力一致的移植胚胎是一种较差的策略,因为它导致整个周期的活产减少。仅报告易位染色体是一种较差的策略,因为它不如对每个染色体进行排名报告以避免不良妊娠。与有针对性的报告相比,排名和排除策略略微减少了完成一个完整周期所需的总体成本和时间.该排名策略避免了12个周期的1次不良妊娠,与排除策略的十分之一相比,排除策略也导致实现活产的妇女减少了22分之一。少数夫妇(<10%)通过避免至少1次不良妊娠而受益,同时也减少了整个周期的时间和成本;大多数夫妇(>70%)除了有针对性的报告外,没有获得任何好处,并且怀孕的结果相同。时间和成本。
结论:对于相互易位的夫妇,PGT-SR的主要目标是避免易位的染色体不平衡产物怀孕,并降低流产的风险,至少是正常核型夫妇的预期。胚泡阶段的滋养外胚层取样并使用NGS进行测试是一种有效的方法;然而,对不相关染色体检测结果异常的胚胎进行排序和排除在移植中是有问题的,并且可能不利于实现活产。有针对性的报告,只有易位涉及的染色体的结果是已知的,应该优先实现活产。应尽最大努力随访和调查PGT-SR后的所有妊娠。一旦知道生殖结果(生化妊娠,临床妊娠,活产),与重排无关的染色体可以作为实验研究进行分析。避免不良妊娠与减少健康分娩机会的风险/收益应该是每对夫妇的决定,并通过适当的遗传咨询来了解他们的特定易位和病史。
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.