Association between maternal MTHFR C677T/A1298C combination polymorphisms and IVF/ICSI outcomes: a retrospective cohort study

STUDY QUESTION: What are the roles of maternal 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C combination polymorphisms on the embryological and clinical outcomes of IVF/ICSI? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: Although many previous studies have explored the association between MTHFR 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. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study investigating 1160 women who were referred for MTHFR 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 MTHFR 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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 (P = 0.007). Moreover, the oocyte maturation rate decreased linearly with the decline in MTHFR enzyme activity determined by combined C677T/A1298C genotypes (P-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 (P = 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. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: We provide a holistic view of the effect of MTHFR C677T and A1298C polymorphisms on the IVF/ICSI outcomes, which can contribute to providing reasonable folic acid supplementation suggestions for women with different MTHFR 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. TRIAL REGISTRATION NUMBER: N/A.