Lu Yong-Jie, Li Qin, Chen Li-Xue, Tian Tian, Kang Jia, Hao Yong-Xiu, Zhou Jian-Suo, Wang Yuan-Yuan, Yan Li-Ying, Li Rong, Chang Liang, Qiao Jie
Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
Hum Reprod Open. 2022 Dec 5;2023(1):hoac055. doi: 10.1093/hropen/hoac055. eCollection 2023.
What are the roles of maternal 5,10-methylenetetrahydrofolate reductase () C677T/A1298C combination polymorphisms on the embryological and clinical outcomes of IVF/ICSI?
Our study reveals for the first time that the oocyte maturation potential gradually decreases with a reduction of maternal MTHFR activity determined by combined C677T/A1298C polymorphisms, while embryo quality was worse in women with intermediate MTHFR activity.
Although many previous studies have explored the association between polymorphisms and IVF/ICSI outcomes, the results remain contradictory due to inadequate samples, no adjustment for potential confounders and/or the study of C677T and A1298C separately. Few studies have systematically investigated the exact role of MTHFR activity determined by combined C677T/A1298C polymorphisms on the embryological and clinical outcomes of IVF/ICSI.
This is a retrospective cohort study investigating 1160 women who were referred for genotyping and IVF/ICSI treatment at Peking University Third Hospital from May 2017 to May 2020.
PARTICIPANTS/MATERIALS SETTING METHODS: Women who were referred for genotyping and their first IVF/ICSI treatment at our hospital were included and those undergoing preimplantation genetic testing cycles were excluded. The included women were divided into different cohorts according to their C677T, A1298C and combined C677T/A1298C genotypes. The embryological outcomes, including oocytes retrieved, metaphase II oocytes, oocyte maturation rate, normal fertilization rate and transplantable embryo rate, were evaluated by generalized linear regression models. The clinical outcomes, including biochemical pregnancy rate, clinical pregnancy rate and live birth rate, were evaluated by log-binomial regression models. All outcomes were adjusted for potential confounders.
Women with the combined 677TT/1298AA genotype (hereafter abbreviated as TT/AA, as with other combined genotypes), whose enzyme activity was the lowest, had a lower oocyte maturation rate compared with those with the wild-type genotype (=0.007). Moreover, the oocyte maturation rate decreased linearly with the decline in MTHFR enzyme activity determined by combined C677T/A1298C genotypes (-trend = 0.001). The combined CC/AC, CC/CC&CT/AA and CT/AC genotypes with intermediate enzyme activity were associated with a lower transplantable embryo rate (=0.013, 0.030 and 0.039, respectively). The differences in clinical outcomes between women with wild-type genotype and combined C677T/A1298C variant genotypes were not significant.
Our study population had comparable embryological outcomes but worse clinical outcomes than other women undergoing IVF/ICSI treatment at our hospital. Therefore, the results related to the clinical outcomes should be generalized with caution. In addition, we did not detect the folate concentration of each patient during pregnancy. However, this might not have much influence on our results because almost all of our study participants took sufficient folic acid around pregnancy.
We provide a holistic view of the effect of C677T and A1298C polymorphisms on the IVF/ICSI outcomes, which can contribute to providing reasonable folic acid supplementation suggestions for women with different genotypes, especially for those with a low oocyte maturation rate and/or low embryo quality.
STUDY FUNDING/COMPETING INTERESTS: This work was funded by the National Natural Science Foundation of China (31871447, and 82101677), the National Key Research and Development Program (2019YFA0801400) and the Natural Science Foundation of Beijing Municipality (7202226). The authors declare that they have no competing interests.
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母体5,10-亚甲基四氢叶酸还原酶（MTHFR）C677T/A1298C联合多态性对体外受精/卵胞浆内单精子注射（IVF/ICSI）的胚胎学和临床结局有何作用？
我们的研究首次揭示，由C677T/A1298C联合多态性所决定的母体MTHFR活性降低时，卵母细胞成熟潜能会逐渐下降，而MTHFR活性中等的女性胚胎质量较差。
尽管此前许多研究探讨了MTHFR多态性与IVF/ICSI结局之间的关联，但由于样本量不足、未对潜在混杂因素进行调整和/或分别研究C677T和A1298C，结果仍相互矛盾。很少有研究系统地调查由C677T/A1298C联合多态性所决定的MTHFR活性对IVF/ICSI胚胎学和临床结局的确切作用。
研究设计、规模、持续时间：这是一项回顾性队列研究，调查了2017年5月至2020年5月在北京大学第三医院接受MTHFR基因分型和IVF/ICSI治疗的1160名女性。
研究对象/材料、环境、方法：纳入在我院接受MTHFR基因分型及首次IVF/ICSI治疗的女性，排除接受植入前基因检测周期的女性。根据其C677T、A1298C及C677T/A1298C联合基因型将纳入的女性分为不同队列。通过广义线性回归模型评估胚胎学结局，包括取卵数、中期II期卵母细胞、卵母细胞成熟率、正常受精率和可移植胚胎率。通过对数二项回归模型评估临床结局，包括生化妊娠率、临床妊娠率和活产率。所有结局均对潜在混杂因素进行了调整。
酶活性最低的677TT/1298AA联合基因型（以下简称为TT/AA，其他联合基因型同理）女性与野生型基因型女性相比，卵母细胞成熟率较低（P = 0.007）。此外，卵母细胞成熟率随C677T/A1298C联合基因型所决定的MTHFR酶活性下降呈线性降低（P趋势 = 0.001）。酶活性中等的CC/AC、CC/CC&CT/AA和CT/AC联合基因型与较低的可移植胚胎率相关（分别为P = 0.013、0.030和0.039）。野生型基因型女性与C677T/A1298C联合变异基因型女性临床结局的差异不显著。
局限性、谨慎原因：我们的研究人群胚胎学结局与我院接受IVF/ICSI治疗的其他女性相当，但临床结局较差。因此，与临床结局相关的结果应谨慎推广。此外，我们未检测每位患者孕期的叶酸浓度。然而，这可能对我们的结果影响不大，因为几乎所有研究参与者在孕期都摄入了足够的叶酸。
我们全面阐述了MTHFR C677T和A1298C多态性对IVF/ICSI结局的影响，这有助于为不同MTHFR基因型的女性，尤其是卵母细胞成熟率低和/或胚胎质量低的女性提供合理的叶酸补充建议。
研究资金/利益冲突：本研究由国家自然科学基金（31871447、82101677）、国家重点研发计划（2019YFA0801400）和北京市自然科学基金（7202226）资助。作者声明无利益冲突。
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