MTHFR gene polymorphisms and methotrexate outcomes in tubal ectopic pregnancy: resolving an evidence–practice paradox

Intramuscular methotrexate (MTX) at 50 mg/m 2 is an established treatment for selected patients with haemodynamically stable tubal ectopic pregnancy. Clinical assessment guides treatment selection, but established predictors do not fully explain variation in response or the occurrence of rare, severe toxicity. Common polymorphisms in methylenetetrahydrofolate reductase (MTHFR), particularly C677T (rs1801133) and A1298C (rs1801131), have therefore been investigated as potential modifiers of MTX outcomes. This structured critical appraisal combines a systematic core search with a narrative synthesis of supplementary evidence. The direct ectopic-pregnancy literature comprised three observational studies and six severe-toxicity case reports, three of which included genotyping. Associations with treatment response were inconsistent, and the only multivariable-adjusted study found no independent genotype association. The toxicity reports lacked suitable comparison groups and genotype-specific treatment denominators and therefore could not establish comparative risk. Interpretation was further limited by small samples, differences in genotyping compartment and treatment exposure, selective post-event testing, and possible publication bias. Although the biochemical rationale is credible, genotype-dependent folate metabolism and MTX handling have not been adequately characterised in ectopic trophoblast at clinically relevant exposures. Current evidence does not support routine pre-treatment MTHFR testing for tubal ectopic pregnancy. Decisions should continue to rely on standard MTX eligibility criteria, established clinical predictors, organ function, medication review, and reliable follow-up. An interim clinical-assessment framework is proposed to organise vigilance, not to define genotype-based treatment or validated toxicity strata. Future research should distinguish maternal from trophoblastic genotype, establish appropriate comparison populations for toxicity, and determine whether genetic information improves clinical decisions beyond established factors.