DOI: 10.4103/jhrs.jhrs_146_26 ISSN: 0974-1208

Role of Paternal Methylenetetrahydrofolate Reductase Polymorphisms on Recurrent Pregnancy Loss and In vitro Fertilisation Outcomes: A Systematic Review and Meta analysis

Kuky Cahya Hamurajib, Mawaddah Ar Rochmah, Dhite Bayu Nugroho, Giovanna Renee Tan, Agung Dewanto
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BSTRACT

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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