Role of Paternal Methylenetetrahydrofolate Reductase Polymorphisms on Recurrent Pregnancy Loss and In vitro Fertilisation Outcomes: A Systematic Review and Meta analysis.
4 affiliations
- 1Department of Obstetrics and Gynecology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada - Dr. Sardjito Hospital, Yogyakarta, Indonesia.
- 2Department of Neurology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
- 3Center for Epidemiology and Biostatistical Unit, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
- 4Department of Internal Medicine, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
Abstract
Background
Paternal methylenetetrahydrofolate reductase (MTHFR) variants may contribute to recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) by compromising sperm DNA integrity and embryonic development.Aim
To examine associations between paternal MTHFR polymorphisms and RPL and/or RIF.Settings and design
This is a systematic review and meta-analysis.Materials and methods
MEDLINE, Cochrane Library and Scopus were searched from 1999 to 27 June 2026. Eligible studies reported odds ratios (ORs) and 95% confidence intervals (CIs) for RPL or RIF in observational designs with a live birth control group. Quality was evaluated using the Newcastle-Ottawa Scale.Statistical analysis used
Meta analyses applied Mendelian inheritance models and subgroup analyses by geographical region.Results
Ten studies were included in the systematic review, and nine in the meta analysis. The dominant model of paternal MTHFR C677T (CT + TT vs. CC genotype) and A1298C (AC + CC vs. AA genotype) were associated with RPL (OR = 1.69; 95% CI: 1.08-2.63; I2 = 71% and OR = 1.72; 95% CI: 1.29-2.30, I2 = 29.4%), particularly in Asian-and Middle Eastern populations (OR = 2.07; 95% CI: 1.05-4.08; subgroup I ² = 75% and OR = 1.87; 95% CI: 1.33-2.62; subgroup I ² = 0%). No significant associations were identified in European populations or with RIF. GRADE certainty was low to very low.Conclusions
Paternal MTHFR C677T and A1298C polymorphisms may be associated with increased RPL risk in Asian and Middle Eastern populations. These exploratory findings warrant adequately powered multiethnic studies that genotype both partners and account for folate status. PROSPERO registration number: CRD42024550497.
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BibTeX
@article{hamurajib2026role,
title = {{Role of Paternal Methylenetetrahydrofolate Reductase Polymorphisms on Recurrent Pregnancy Loss and In vitro Fertilisation Outcomes: A Systematic Review and Meta analysis.}},
author = {Kuky Cahya Hamurajib and Mawaddah Ar Rochmah and Dhite Bayu Nugroho and Giovanna Renee Tan and Agung Dewanto},
journal = {Journal of human reproductive sciences},
year = {2026},
month = jul,
doi = {10.4103/jhrs.jhrs_146_26},
url = {https://europepmc.org/article/MED/42924326},
note = {CC BY-NC-SA},
}
RIS
TY - JOUR
TI - Role of Paternal Methylenetetrahydrofolate Reductase Polymorphisms on Recurrent Pregnancy Loss and In vitro Fertilisation Outcomes: A Systematic Review and Meta analysis.
AU - Kuky Cahya Hamurajib
AU - Mawaddah Ar Rochmah
AU - Dhite Bayu Nugroho
AU - Giovanna Renee Tan
AU - Agung Dewanto
PY - 2026
DA - 2026/07/01
JO - Journal of human reproductive sciences
DO - 10.4103/jhrs.jhrs_146_26
UR - https://europepmc.org/article/MED/42924326
AB - Background Paternal methylenetetrahydrofolate reductase (MTHFR) variants may contribute to recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) by compromising sperm DNA integrity and embryonic development.Aim To examine associations between paternal MTHFR polymorphisms and RPL and/or RIF.Settings and design This is a systematic review and meta-analysis.Materials and methods MEDLINE, Cochrane Library and Scopus were searched from 1999 to 27 June 2026. Eligible studies reported odds ratios (ORs) and 95% confidence intervals (CIs) for RPL or RIF in observational designs with a live birth control group. Quality was evaluated using the Newcastle-Ottawa Scale.Statistical analysis used Meta analyses applied Mendelian inheritance models and subgroup analyses by geographical region.Results Ten studies were included in the systematic review, and nine in the meta analysis. The dominant model of paternal MTHFR C677T (CT + TT vs. CC genotype) and A1298C (AC + CC vs. AA genotype) were associated with RPL (OR = 1.69; 95% CI: 1.08-2.63; I2 = 71% and OR = 1.72; 95% CI: 1.29-2.30, I2 = 29.4%), particularly in Asian-and Middle Eastern populations (OR = 2.07; 95% CI: 1.05-4.08; subgroup I ² = 75% and OR = 1.87; 95% CI: 1.33-2.62; subgroup I ² = 0%). No significant associations were identified in European populations or with RIF. GRADE certainty was low to very low.Conclusions Paternal MTHFR C677T and A1298C polymorphisms may be associated with increased RPL risk in Asian and Middle Eastern populations. These exploratory findings warrant adequately powered multiethnic studies that genotype both partners and account for folate status. PROSPERO registration number: CRD42024550497.
SN - 0974-1208
SN - 1998-4766
ER -