Pregnancy Outcomes Following Paternal Methotrexate Exposure: A Systematic Review and Meta-Analysis

Evidence guiding the management of pregnancies fathered by men exposed to methotrexate (MTX) remains limited. This systematic review and meta-analysis evaluated whether paternal MTX exposure before or at conception is associated with major congenital malformations or other adverse pregnancy outcomes.

PubMed, Web of Science, and Reprotox were searched from inception to May 2025, supplemented by manual reference screening.

Eligible studies were cohort or case-control designs assessing paternal MTX exposure during preconception or conception period with an unexposed control group. Reviews, editorials, animal studies, case reports, and overlapping datasets were excluded.

Study selection and data extraction were conducted independently. Risk of bias was assessed with ROBINS-I, quality with the Newcastle-Ottawa Scale, and certainty of evidence with GRADE. Adjusted odds ratios (aORs) were used for random-effects meta-analysis; outcomes lacking sufficient data were narratively synthesized. The primary outcome was major congenital malformations following paternal MTX exposure. Secondary outcomes included cardiac malformations, spontaneous abortion, live birth, elective termination, stillbirth, and preterm birth.

No increased risks were observed for congenital malformations (aOR 1.00; 95% CI 0.62-1.61; I² = 0%), stillbirth (OR 0.85; 95% CI 0.11-6.45; I² = 0%), or preterm birth (OR 0.95; 95% CI 0.59-1.53; I² = 26%). In the qualitative review of case reports, case series, and noncomparable cohort data, no consistent or recurring patterns of malformations were identified.

Paternal MTX exposure was not associated with increased risks of congenital malformations, stillbirth, or preterm birth, nor with a consistent or recurrent pattern of anomalies. These findings provide reassurance regarding fetal safety following paternal MTX exposure.