亲本核型P-556结构重排及其对胚胎能力的影响。290个PGT-SR循环分析

IF 6 1区医学 Q1 OBSTETRICS & GYNECOLOGY

Human reproduction Pub Date : 2025-06-28 DOI:10.1093/humrep/deaf097.862

J Pla Victori, D Cimadomo, O Osetti, P Petrone, V Vergara, M Cruz, J Reina, C Marín, E Fernandez, S Caroselli, L Picchetta, L Rienzi, F M Ubaldi, A Capalbo, A Vaiarelli

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Prior studies have estimated the prevalence of unbalanced derivatives on sperm samples and transferrable embryo rate after PGT-SR, even for each SR subtype. However, many published studies on PGT-SR results are limited by small sample size. Moreover, the potential interchromosomal effect of SRs on aneuploidy remains debated. Furthermore, the exact effect of SRs on blastocyst development and aneuploidy rate remain greatly unexplored. Study design, size, duration Retrospective observational cohort study including 290 PGT-SR cycles (Robertsonian-translocations: N = 39 maternal, N = 54 paternal; Reciprocal-translocations: N = 61 maternal, N = 55, paternal; Inversion/deletions/duplications: N = 33 maternal, N = 48 paternal) conducted at a private IVF clinic (years 2014-2023). 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引用次数: 0

摘要

亲本核型的结构重排（SR）对囊胚发育和非整倍率的影响是什么？SRs（尤其是双向易位）使整个孕龄的囊胚率恶化。在囊胚≥1个的夫妇中，基线非整倍体率为60%（35岁），由于母亲年龄较大而进一步增加。已知的已经平衡的SR携带者面临着由于胚胎形成不平衡而增加的不育、复发性流产和后代出生缺陷的风险。PGT-SR通过允许鉴定和选择整倍体和平衡胚胎来帮助减轻这些风险。先前的研究估计了PGT-SR后精子样本中不平衡衍生物的患病率和可移植胚胎率，即使对于每种SR亚型也是如此。然而，许多已发表的关于PGT-SR结果的研究受样本量小的限制。此外，SRs对非整倍体的潜在染色体间效应仍存在争议。此外，SRs对囊胚发育和非整倍体率的确切影响仍未得到充分研究。研究设计、规模、持续时间回顾性观察队列研究包括290个PGT-SR周期(罗伯逊易位：N = 39名母亲，N = 54名父亲；相互易位：N = 61，母位，N = 55，父位；倒置/缺失/重复：在一家私人试管婴儿诊所（2014-2023年）进行的N = 33名母亲，N = 48名父亲。我们分析了SR类型和携带者性别（对广义估计方程中的混杂因素进行了调整）对每个mii卵母细胞的囊胚率、每个活检囊胚的非整倍性率和每个周期结果（在结束的尝试中获得≥1个囊胚和≥1个活产）的影响[=累积活产率，cLBR]。170对夫妇共290个周期（年龄：36.2±4.7岁，BMI:22.1±3.7 Kg/m2, AMH:2.1±1.4 ng/ml，无妊娠71%，精子浓度：12±13百万/ml，精子A+ b活力：46%±19%，精子正常形态：4±3%），共检索到2958个卵母细胞复合物。一直采用gnrh拮抗剂方案。在96%和98%的周期中，分别使用新鲜的自体卵母细胞和射精精子。我们进行了ICSI （N = 2115个mii卵母细胞）、单囊胚培养、滋养外胚层活检（不进行第3天透明带钻孔）、综合染色体检测（N = 751个囊胚）和玻璃化加热单整倍体移植（N = 168）。主要结果和机会的作用携带父亲- srs的夫妇与携带母亲- srs的夫妇年龄较大，精子参数较差，无论sr类型如何。母亲sr携带者的中位卵母细胞成熟率为75%，而核型正常的女性为78% （p=NS）。无论母亲年龄和精子参数如何，PGT-SR周期的囊胚率始终低于正常核型夫妇的历史对照。往复易位加剧了这一趋势，与sr携带者的性别无关，进一步降低了获得≥1个囊胚的机会(往复易位：65%，罗伯逊易位：81%；校正混杂因素OR =0.23,95%CI:0.09-0.59,p=0.002)。在35岁的女性中，每个活检胚泡的基线非整倍率为60%，到39岁时增加到80%，到35岁时增加到80%。≥42岁时90%。这一趋势与sr型和携带者性别无关。与我们的历史对照PGT-A周期相比，该曲线在整个母亲年龄期间始终较高。具体来说，我们报告了恒定的35%的非整倍体率与重排的染色体携带的患者。相反，没有染色体间效应的报道，其他非整倍体遵循预期曲线随着母亲年龄的增加。每ET的LBR为44%，与PGT-A后的整倍体转移相当。仅在相互易位的携带者（经年龄、精子参数和人工授精的mii -卵母细胞调整的OR =0.26,95%CI:0.15-0.47,p<0.001）中，无论携带者性别，cLBR均显著低于历史PGT-A对照。局限性，谨慎的原因回顾性单中心研究，样本量有限，特别是亚分析。我们计划通过多中心和多国合作收集更多数据，以增加样本量和证据的普遍性。在咨询过程中，父母SRs对胚胎发育能力和非整倍体率的影响的定义对于正确估计一对夫妇活产的机会和相应地定制试管婴儿策略至关重要。在一些情况下，多周期咨询方法可能是有益的。试验注册号

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P-556 Structural rearrangements in parental karyotypes and their impact on embryo competence. Analysis of 290 PGT-SR cycles

Study question What is the impact of structural rearrangements (SR) in parental karyotypes on blastocyst development and aneuploidy-rates? Summary answer SRs (especially reciprocal-translocations) worsen blastulation-rate throughout maternal age. Among couples with ≥1 blastocyst, baseline aneuploidy-rate is 60% (<35 years) further increasing due to advanced-maternal-age. What is known already Balanced SR carriers face increased risk of infertility, recurrent miscarriages, and offspring with birth defects due to unbalanced embryos being formed. PGT-SR helps mitigate these risks by allowing the identification and selection of euploid and balanced embryos. Prior studies have estimated the prevalence of unbalanced derivatives on sperm samples and transferrable embryo rate after PGT-SR, even for each SR subtype. However, many published studies on PGT-SR results are limited by small sample size. Moreover, the potential interchromosomal effect of SRs on aneuploidy remains debated. Furthermore, the exact effect of SRs on blastocyst development and aneuploidy rate remain greatly unexplored. Study design, size, duration Retrospective observational cohort study including 290 PGT-SR cycles (Robertsonian-translocations: N = 39 maternal, N = 54 paternal; Reciprocal-translocations: N = 61 maternal, N = 55, paternal; Inversion/deletions/duplications: N = 33 maternal, N = 48 paternal) conducted at a private IVF clinic (years 2014-2023). We analyzed the impact of SR type and carriers’ sex (adjusted for confounders in generalized-estimating-equations) on blastulation-rate per MII-oocytes, aneuploidy-rates per biopsied blastocysts and outcomes per cycle (≥1 blastocyst obtained and ≥1 live-birth achieved among concluded attempts [= cumulative-live-birth rate, cLBR]). Participants/materials, setting, methods 290 cycles conducted by 170 couples (Age:36.2±4.7 years, BMI:22.1±3.7 Kg/m2, AMH:2.1±1.4 ng/ml, 71% nulligravida, sperm concentration:12±13 millions/ml, sperm A+B-motility:46%±19%, sperm normal morphology:4±3%) retrieving 2958 cumulus-oocyte-complexes. GnRH-antagonist protocols were always adopted. In 96% and 98% of cycles fresh own-oocytes and ejaculated-sperm were used, respectively. We conducted ICSI (N = 2115 MII-oocytes), single blastocyst culture, trophectoderm biopsy without day3 zona-pellucida drilling, comprehensive chromosome testing (N = 751 blastocysts), and vitrified-warmed single euploid transfer (N = 168). Main results and the role of chance Couples carrying paternal-SRs versus maternal-SRs were older with poorer sperm parameters, regardless SR-type. Median oocyte maturation-rate among maternal-SR carriers was 75% versus 78% among women with normal karyotypes (p=NS). The blastulation-rate among PGT-SR cycles was consistently lower than our historical control of couples with normal karyotypes, throughout maternal age and regardless of sperm parameters. Reciprocal-translocations exacerbated this trend, independently of SR-carriers’ sex, further reducing the chance of obtaining ≥1 blastocyst (Reciprocal-translocations:65% versus Robertsonian-translocations:81%; OR adjusted for confounders=0.23,95%CI:0.09-0.59,p=0.002). The baseline aneuploidy-rate per biopsied blastocyst was 60% in women <35, increasing to 80% by 39 and to > 90% at ≥ 42 years. This trend was independent of SR-type and carriers’ sex. Compared to our historical control of PGT-A cycles, this curve was consistently higher throughout maternal age. Specifically, we reported a constant »35% rate of aneuploidies related with the rearranged chromosomes carried by the patients. Instead, no inter-chromosomal effect was reported with other aneuploidies following the expected curve with increasing maternal age. The LBR per ET was 44%, comparable to euploid transfers after PGT-A. cLBR was significantly lower than our historical PGT-A controls only among reciprocal translocations’ carriers (OR adjusted for age, sperm parameters and inseminated MII-oocytes =0.26,95%CI:0.15-0.47,p<0.001) regardless of carriers’ sex. Limitations, reasons for caution Retrospective single center study with a limited sample size especially for sub-analyses. We plan to increase the sample size and the generalizability of the evidence by collecting more data through a multicenter and multinational collaboration. Wider implications of the findings During counselling, the definition of parental SRs’ impact on embryo developmental competence and aneuploidy rate is crucial to properly estimate couple-specific chance of live-birth and tailor IVF strategies accordingly. In several scenarios, a multi-cycle counseling approach might be beneficial. Trial registration number No

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来源期刊

Human reproduction 医学-妇产科学

CiteScore

10.90

自引率

6.60%

发文量

1369

审稿时长

1 months

期刊介绍： Human Reproduction features full-length, peer-reviewed papers reporting original research, concise clinical case reports, as well as opinions and debates on topical issues. Papers published cover the clinical science and medical aspects of reproductive physiology, pathology and endocrinology; including andrology, gonad function, gametogenesis, fertilization, embryo development, implantation, early pregnancy, genetics, genetic diagnosis, oncology, infectious disease, surgery, contraception, infertility treatment, psychology, ethics and social issues.