Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2021 Sep;38(9):2237-2249.
doi: 10.1007/s10815-021-02236-8. Epub 2021 May 25.

Effect of polymorphisms of MTHFR in controlled ovarian stimulation: a systematic review and meta-analysis

Xinrui Wang  1 , Ximu Sun  1 , Borui Tang  2 , Lihong Liu  3 , Xin Feng  4
Affiliations
Meta-Analysis

Effect of polymorphisms of MTHFR in controlled ovarian stimulation: a systematic review and meta-analysis

Xinrui Wang et al. J Assist Reprod Genet. 2021 Sep.

Abstract

Objective: Although several studies have reported a potential impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on controlled ovarian stimulation (COS), the results remain controversial. The aim of the systematic review and meta-analysis was to evaluate the effect of MTHFR polymorphism on COS outcomes.

Methods: PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials databases were searched up to December 2, 2020. COS clinical outcomes based on gene polymorphisms were included. Two reviewers independently extracted the data. The primary outcome was the number of oocytes retrieved. The secondary outcomes were the number of metaphase II (MII) oocytes, stimulation duration, basal follicle-stimulating hormone (FSH) level, FSH dosage, positive pregnancy test, ongoing pregnancy rate, clinical pregnancy rate, miscarriage rate, and live birth rate. Meta-analysis was performed using a fixed-effect model or random-effect model with Review Man 5.3.5. Mean difference (MD) with 95% confidence intervals (95%CIs) was calculated for continuous outcomes. The quality assessment of included studies was evaluated by using the Newcastle-Ottawa Scale.

Results: Eleven studies were included in the systematic review, and seven studies with 2015 participants were included in the meta-analysis. Basal FSH level was significantly lower in CC homozygotes than TT homozygotes (four studies, 867 participants, MD - 0.54, 95%CI - 0.85 to - 0.23, P = 0.0006; I2 = 0%) of MTHFR (rs1801133). FSH dose was significantly fewer in CC homozygotes compared with CT heterogeneous (three studies, 949 participants, MD - 75.78, 95%CI - 135.23 to - 16.33, P = 0.01; I2 = 32%) or CT/TT model (three studies, 1097 participants, MD - 80.18, 95%CI - 135.54 to - 24.81, P = 0.005; I2 = 42%). Differences in the oocytes retrieved and stimulation duration were insignificant. Gene variants on MTHFR (rs1801133) and MTHFR (rs1801131) were reported in ongoing pregnancy rate, clinical pregnancy rate, and live birth rate.

Conclusion: Studies to date indicate that polymorphisms of MTHFR could influence basal FSH level and FSH dose. The results could be useful to promote clinical practice on COS protocols. Further studies are needed to evaluate the clinical relevance of the multigene combination on COS.

Keywords: Controlled ovarian stimulation; FSH; MTHFR; Meta-analysis; Methylenetetrahydrofolate reductase; Oocytes retrieved; Polymorphism.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flow diagram of study selection for the systematic review and meta-analysis
Fig. 2
Fig. 2
Forest plots of differences among MTHFR (rs1801133) genotype carriers regarding the number of oocytes retrieved. A: dominant model; B: homozygote model; C: heterozygote model; D: recessive model
Fig. 3
Fig. 3
Forest plots of differences among MTHFR (rs1801133) genotype carriers regarding stimulation duration. A: dominant model; B: homozygote model; C: heterozygote model; D: recessive model
Fig. 4
Fig. 4
Forest plots of differences among MTHFR (rs1801133) genotype carriers regarding basal FSH level. A: dominant model; B: homozygote model; C: heterozygote model; D: recessive model
Fig. 5
Fig. 5
Forest plots of differences among MTHFR (rs1801133) genotype carriers regarding FSH dose. A: dominant model; B: homozygote model; C: heterozygote model; D: recessive model
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Alviggi C, Humaidan P, Ezcurra D. Hormonal, functional and genetic biomarkers in controlled ovarian stimulation: tools for matching patients and protocols. Reprod Biol Endocrinol. 2012;10:9. doi: 10.1186/1477-7827-10-9. - DOI - PMC - PubMed
    1. Shrestha D, La X, Feng HL. Comparison of different stimulation protocols used in in vitro fertilization: a review. Ann Transl Med. 2015;3(10):137. doi: 10.3978/j.issn.2305-5839.2015.04.09. - DOI - PMC - PubMed
    1. Song D, Huang XL, Hong L, Yu JM, Zhang ZF, Zhang HQ, et al. Sequence variants in FSHR and CYP19A1 genes and the ovarian response to controlled ovarian stimulation. Fertil Steril. 2019;112(4):749–57.e2. doi: 10.1016/j.fertnstert.2019.05.017. - DOI - PubMed
    1. Lindgren I, Bååth M, Uvebrant K, Dejmek A, Kjaer L, Henic E, Bungum M, Bungum L, Cilio C, Leijonhufvud I, Skouby S, Andersen CY, Giwercman YL. Combined assessment of polymorphisms in the LHCGR and FSHR genes predict chance of pregnancy after in vitro fertilization. Hum Reprod. 2016;31(3):672–683. doi: 10.1093/humrep/dev342. - DOI - PubMed
    1. König TE, van der Lee J, Schats R, Lambalk CB. The relationship between FSH receptor polymorphism status and IVF cycle outcome: a retrospective observational study. Reprod BioMed Online. 2019;39(2):231–240. doi: 10.1016/j.rbmo.2019.05.018. - DOI - PubMed

Substances

LinkOut - more resources