Abstract：
OBJECTIVE: Despite advances in assisted reproductive technologies, many blastocysts are lost unexpectedly during implantation. Alterations in maternal immune tolerance towards fetal antigens may contribute to adverse IVF outcomes. The purpose of this study is to evaluate whether administering Granulocyte Colony-Stimulating Factor (G-CSF) to couples with a Human Leukocyte Antigen/Killer-Cell Immunoglobulin-Like Receptor (HLA/KIR) mismatch could positively modulate the implantation process in patients with recurrent implantation failure (RIF). A KIR/HLA-C mismatch occurs when the interaction between KIRs and HLA-C causes an inhibition of NK cells, which may result in reduced G-CSF secretion leading to impaired placentation and increased risk of miscarriage, pre-eclampsia and fetal growth restriction.
METHODS: A retrospective monocentric cohort study conducted at the IVI Clinic in Rome, including women with a history of at least two failed blastocyst transfers. Couples underwent KIR and HLA-C testing. Couples with a KIR/HLA-C mismatch received G-CSF subcutaneously up to week nine of gestation. The mismatch included cases with inhibitory KIR genotypes and HLA-C2C2 females with HLA-C1C1, or C1C2 males or HLA-C1C2 females with male HLA-C2C2. The reproductive outcomes were assessed, and the logistic regression models controlled for potential confounders affecting IVF outcomes.
RESULTS: 79 patients with RIF and a KIR/HLA-C mismatch were included in the study. 30 patients were administered G-CSF, and 49 received no treatment. In the univariate analysis, no statistically significant differences were reported in the reproductive outcomes after IVF between the women treated with G-CSF and the control group. However, the logistic regression analysis that controlled for confounding factors showed that patients treated with subcutaneous G-CSF had statistically significant higher ongoing-pregnancy (aOR=3.808) and live-birth (aOR=4.998) rates, and a lower miscarriage rate (aOR=0.057). No statistically significant differences were found in other reproductive outcomes.
CONCLUSIONS: The use of subcutaneous G-CSF in patients with a KIR/HLA-C mismatch undergoing IVF may reduce miscarriage and improve live-birth rates. G-CSF may modulate NK-mediated immune mechanisms and improve trophoblast invasion and development. Randomized trials are warranted to validate these findings and enhance the chances of successful pregnancies in couples with an immunological mismatch.
METHODS: A retrospective monocentric cohort study conducted at the IVI Clinic in Rome, including women with a history of at least two failed blastocyst transfers. Couples underwent KIR and HLA-C testing. Couples with a KIR/HLA-C mismatch received G-CSF subcutaneously up to week nine of gestation. The mismatch included cases with inhibitory KIR genotypes and HLA-C2C2 females with HLA-C1C1, or C1C2 males or HLA-C1C2 females with male HLA-C2C2. The reproductive outcomes were assessed, and the logistic regression models controlled for potential confounders affecting IVF outcomes.
RESULTS: 79 patients with RIF and a KIR/HLA-C mismatch were included in the study. 30 patients were administered G-CSF, and 49 received no treatment. In the univariate analysis, no statistically significant differences were reported in the reproductive outcomes after IVF between the women treated with G-CSF and the control group. However, the logistic regression analysis that controlled for confounding factors showed that patients treated with subcutaneous G-CSF had statistically significant higher ongoing-pregnancy (aOR=3.808) and live-birth (aOR=4.998) rates, and a lower miscarriage rate (aOR=0.057). No statistically significant differences were found in other reproductive outcomes.
CONCLUSIONS: The use of subcutaneous G-CSF in patients with a KIR/HLA-C mismatch undergoing IVF may reduce miscarriage and improve live-birth rates. G-CSF may modulate NK-mediated immune mechanisms and improve trophoblast invasion and development. Randomized trials are warranted to validate these findings and enhance the chances of successful pregnancies in couples with an immunological mismatch.
摘要：
目标：尽管辅助生殖技术取得了进展，许多胚泡在植入过程中意外丢失。母体对胎儿抗原免疫耐受的改变可能导致不良的IVF结局。这项研究的目的是评估将粒细胞集落刺激因子（G-CSF）与人白细胞抗原/杀伤细胞免疫球蛋白样受体（HLA/KIR）错配配对是否可以积极调节患者的植入过程复发性植入失败（RIF）。KIR/HLA-C错配发生时，KIR和HLA-C之间的相互作用引起抑制NK细胞，这可能导致G-CSF分泌减少，导致胎盘形成受损和流产风险增加，先兆子痫和胎儿生长受限。
方法：在罗马的IVI诊所进行的回顾性单中心队列研究，包括有至少两次囊胚移植失败病史的女性。夫妇接受了KIR和HLA-C测试。KIR/HLA-C错配的夫妇皮下接受G-CSF，直至妊娠9周。错配包括抑制性KIR基因型和HLA-C2C2女性与HLA-C1C1，或C1C2男性或HLA-C1C2女性与男性HLA-C2C2。评估了生殖结果，以及对影响IVF结局的潜在混杂因素进行控制的逻辑回归模型。
结果：79例RIF和KIR/HLA-C错配患者被纳入研究。30例患者给予G-CSF，49人没有接受治疗。在单变量分析中，在接受G-CSF治疗的妇女与对照组之间,IVF后的生殖结局无统计学差异.然而,控制混杂因素的logistic回归分析显示，皮下G-CSF治疗的患者有更高的持续妊娠率(aOR=3.808)和活产率(aOR=4.998)，和较低的流产率（aOR=0.057）。在其他生殖结果中没有发现统计学上的显着差异。
结论：在接受IVF的KIR/HLA-C不匹配患者中使用皮下G-CSF可以减少流产并提高活产率。G-CSF可以调节NK介导的免疫机制并改善滋养细胞的侵袭和发育。有必要进行随机试验以验证这些发现，并提高免疫错配夫妇成功怀孕的机会。
方法：在罗马的IVI诊所进行的回顾性单中心队列研究，包括有至少两次囊胚移植失败病史的女性。夫妇接受了KIR和HLA-C测试。KIR/HLA-C错配的夫妇皮下接受G-CSF，直至妊娠9周。错配包括抑制性KIR基因型和HLA-C2C2女性与HLA-C1C1，或C1C2男性或HLA-C1C2女性与男性HLA-C2C2。评估了生殖结果，以及对影响IVF结局的潜在混杂因素进行控制的逻辑回归模型。
结果：79例RIF和KIR/HLA-C错配患者被纳入研究。30例患者给予G-CSF，49人没有接受治疗。在单变量分析中，在接受G-CSF治疗的妇女与对照组之间,IVF后的生殖结局无统计学差异.然而,控制混杂因素的logistic回归分析显示，皮下G-CSF治疗的患者有更高的持续妊娠率(aOR=3.808)和活产率(aOR=4.998)，和较低的流产率（aOR=0.057）。在其他生殖结果中没有发现统计学上的显着差异。
结论：在接受IVF的KIR/HLA-C不匹配患者中使用皮下G-CSF可以减少流产并提高活产率。G-CSF可以调节NK介导的免疫机制并改善滋养细胞的侵袭和发育。有必要进行随机试验以验证这些发现，并提高免疫错配夫妇成功怀孕的机会。
