The association of parental methylenetetrahydrofolate reductase polymorphisms (MTHFR 677C > T and 1298A > C) and fetal loss: a case–control study in South Australia

Abstract

Objective: To determine the association between parental MTHFR 677C > T (RS1801133) and 1298A > C (RS1801131), and fetal loss (FL).

Design: Case–control study.

Setting: Department of Obstetrics and Gynecology, Lyell McEwin Hospital (LMH), and the Women’s and Children’s Hospital (WCH) in Adelaide, Australia.

Patients: A total of 222 couples with FL and 988 couples with uncomplicated pregnancies.

Measurements: The main outcomes were FL and hyperhomocysteinemia (HHcy). All couples were tested for MTHFR 677C > T and 1298A > C. Fasting homocysteine was measured in the women with FL.

Results: The main finding was a significant difference between the FL group and controls in couples with ≥4 abnormal alleles compared to <4 [p=.0232, OR 1.9 (95% CI 1.1–3.3)]. None of the couples with FL had zero abnormal alleles (both parents 677CC/1298 AA). However, this was also rare amongst the controls. Maternal carriage of both 677C > T and the 1298A > C polymorphisms was similar between the FL group and controls. The prevalence of paternal 677TT/1298AA and 677CC/1298AC was significantly higher in the FL group compared with controls. HHcy was significantly more common in the FL group compared with controls.

Conclusion: The presence of parental MTHFR 677C > T and 1298A > C is associated with FL. The association between maternal MTHFR genotypes with FL is less pronounced than in previously published articles investigating first trimester miscarriages. Maternal HHcy is a significant risk factor for FL.

Keywords:

• Fetal loss
• hyperhomocysteinemia
• methylenetetrahydrofolate reductase
• MTHFR
• pregnancy loss

Disclosure statement

The authors report no conflicts of interest.

Data availability statement

The data that support the findings of this study are available on request from the corresponding author, BK. The data are not publicly available due to restrictions in ethics approval, where there was no specific consent from women to make the data publically available. This is to preserve the privacy of research participants.

Acknowledgements

We thank the women and men who participated in the study. We thank the Australian Genome Research Facility (AGRF) for conducting the genotyping.

Additional information

Funding

This work was supported by a National Health and Medical Research Council of Australia (NHMRC) project grant (GNT519225) awarded to CR and GD. CR was supported by a NHMRC Senior research fellowship (GNT1020749). PA is supported by a NHMRC Peter Doherty BioMedical Postdoctoral fellowship (GNT1090778).