基于波塞冬标准的卵巢低反应人群胚胎非整倍体率分析

Blastocyst aneuploidy rates in poor ovarian response patients according to the POSEIDON criteria

目的基于波塞冬标准分析卵巢低反应(poor ovarian response,POR)人群的胚胎非整倍体率,探究卵巢储备评估指标对卵子质量的预测价值。方法基于2017年1月至2020年12月期间于山东大学附属生殖医院生殖遗传科行胚胎移植前非整倍体筛查(preimplantation genetic testing for aneuploidies,PGT-A)助孕的患者临床资料,进行回顾性病例对照研究。根据年龄和卵巢储备水平参照波塞冬标准分为POR 1组,即非高龄非预期POR组[年龄<35岁,抗苗勒管激素(anti-Müllerian hormone,AMH)≥1.2μg/L,获卵数≤9枚,258个周期];POR 2组,即高龄非预期POR组(年龄≥35岁,AMH≥1.2μg/L,获卵数≤9枚,397个周期);POR 3组,即非高龄低储备组(年龄<35岁,AMH<1.2μg/L,获卵数≤9枚,99个周期);POR 4组,即高龄低储备组(年龄≥35岁,AMH<1.2μg/L,获卵数≤9枚,377个周期)。以年龄为匹配因素,选取卵巢储备及卵巢反应均正常女性设立非POR组作为对照(非POR 1组、非POR 2组、非POR 3组和非POR 4组,AMH≥1.2μg/L,获卵数>9枚)。根据各组样本量差异,对非高龄组进行1∶2倾向性评分匹配(propensity score matching,PSM;POR 1组比非POR 1组;POR 3组比非POR 3组),高龄组进行1∶1 PSM(POR 2组比非POR 2组;POR 4组比非POR 4组)。胚胎整倍体率和非整倍体率作为主要观察指标,获卵数、MⅡ(成熟卵子)数、双原核(two pronuclei,2PN)数、检测囊胚数、胚胎整倍体数、非整倍体数、嵌合体胚胎数/率作为次要观察指标。结果POR 1~4组的获卵数[7.0(6.0,9.0)枚、7.0(5.0,8.0)枚、6.0(4.0,9.0)枚和5.0(3.0,7.0)枚]和检测囊胚数[3.0(2.0,4.0)枚、2.0(1.0,3.0)枚、3.0(2.0,4.0)枚和2.0(1.0,3.0)枚]均显著少于同龄非POR 1~4组[获卵数:16.0(13.0,20.0)枚、14.0(11.0,17.0)枚、16.0(13.0,20.0)枚、13.0(11.0,17.0)枚,均P<0.001;检测囊胚数:4.0(3.0,6.0)枚、3.0(2.0,5.0)枚、4.0(3.0,6.0)枚、3.0(2.0,5.0)枚,均P<0.001]。非POR 4组在校正重复取卵周期、PGT-A指征、促排卵方案和促性腺激素用量后,POR 4组胚胎非整倍体率显著高于非POR 4组(OR=1.252,95%CI:1.053~1.488,P=0.011),POR 1组、2组、3组患者与相应的非POR 1、2、3组相比,胚胎非整倍体率差异均无统计学意义(均P>0.05)。结论高龄(≥35岁)女性卵巢储备异常降低不仅减少了获卵数,而且因影响卵子质量进而导致胚胎整倍体率下降、非整倍体率上升;而非高龄(<35岁)女性卵巢储备降低主要影响获卵数。

Objective To compare the aneuploidy rate of embryos between poor ovarian response(POR)patients and women with normal ovarian reserve stratified by age,and to eliminate the influence of ovarian reserve on embryo quality.Methods This was a retrospective case-control study of patients who underwent preimplantation genetic testing for aneuploidies(PGT-A)at the Department of Reproduction and Genetics in Hospital for Reproductive Medicine,Shandong University from January 2017 to December 2020.According to the POSEIDON criteria,POR patients were divided into group 1[age<35 years,anti-Müllerian hormone(AMH)≥1.2μg/L,number of oocytes retrieved≤9,258 cycles],group 2(age≥35 years,AMH≥1.2μg/L,number of oocytes retrieved≤9,397 cycles),group 3(age<35 years,AMH<1.2μg/L,number of oocytes retrieved≤9,99 cycles)and group 4(age≥35 years,AMH<1.2μg/L,number of oocytes retrieved≤9,377 cycles).The aneuploidy rate of the blastocysts in each group was compared with age-matched control women with normal ovarian reserve and normal ovarian response(non-POR 1 group,non-POR 2 group,non-POR 3 group and non-POR 4 group,AMH≥1.2μg/L,number of oocytes retrieved>9).Based on the difference in sample size of POR groups and control groups,a 1∶2 propensity score matching(PSM)analysis was performed between the<35 years old POR groups and age-matched control groups(POR 1 group vs.non-POR 1 group,POR 3 group vs.non-POR 3 group)and a 1∶1 PSM analysis was performed between the≥35 years old POR groups and age-matched control groups(POR 2 group vs.non-POR 2 group,POR 4 group vs.non-POR 4 group).The main outcomes were the rates of euploid and aneuploid embryo,the secondary outcomes were the numbers of oocytes retrieved,metaphaseⅡoocytes,two pronuclei,embryos biopsied,euploid embryos,aneuploid embryos and mosaic embryos per cycle.ResultsThe number of oocytes retrieved and embryos biopsied embryos in POR 1-4 groups was significantly decreased compared with non-POR 1-4 groups[No.of oocytes retrieved:7.0(6.0,9.0)vs.16.0(13.0,20.0),7.0(5.0,8.0)vs.14.0(11.0,17.0),6.0(4.0,9.0)vs.16.0(13.0,20.0),5.0(3.0,7.0)vs.13.0(11.0,17.0),all P<0.001;No.of embryos biopsied:3.0(2.0,4.0)vs.4.0(3.0,6.0),2.0(1.0,3.0)vs.3.0(2.0,5),3.0(2.0,4.0)vs.4.0(3.0,6.0),2.0(1.0,3.0)vs.3.0(2.0,5.0),all P<0.001].After adjusting for repeated egg retrieval,PGT-A indications,ovarian stimulation protocol and total dosage of gonadotrophin,the embryo aneuploidy rate in group 4 POR patients was significantly higher than controls(OR=1.252,95%CI:1.053-1.488,P=0.011).However,no differences were identified in embryo aneuploidy rate between POR patients in groups 1,2,3 and corresponding controls,respectively(all P>0.05).Conclusion The ovarian reserve adversely affects the quantity and quality of oocytes in advanced age POR women(≥35 years old).Decreased ovarian reserve in young women(<35 years old)mainly affects the number of oocytes retrieved.