Pregnancy Outcomes Following Paternal Methotrexate Exposure: A Systematic Review and Meta‐Analysis
Bibliographic record
Abstract
OBJECTIVE: 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. DATA SOURCES: PubMed, Web of Science, and Reprotox were searched from inception to May 2025, supplemented by manual reference screening. STUDY ELIGIBILITY CRITERIA: 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. METHODS: 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. RESULTS: = 26%). In the qualitative review of case reports, case series, and noncomparable cohort data, no consistent or recurring patterns of malformations were identified. CONCLUSIONS: 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.013 | 0.037 |
| Meta-epidemiology (narrow) | 0.003 | 0.001 |
| Meta-epidemiology (broad) | 0.014 | 0.031 |
| Bibliometrics | 0.006 | 0.006 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".