Timing of conception after methotrexate and subsequent pregnancy outcomes: A retrospective cohort study

Methotrexate is widely used to treat ectopic pregnancy (EP). Concerns about its teratogenicity have led to uncertainty regarding the optimal interval before attempting conception. Guidelines recommend a 3-month washout period, while the manufacturer advises 6 months. Evidence on the safety of early conception is limited. We aimed to evaluate whether conception within 1-3 months after methotrexate treatment for EP is as safe as conception after longer intervals.

We conducted a retrospective cohort study of women treated with 30-150 mg methotrexate for ectopic pregnancy in Clalit Health Services hospitals (2010-2021). Subsequent pregnancies were categorized by time from treatment to conception. Outcomes included major congenital malformations, spontaneous abortion, preterm birth, and low birth weight. Adjusted odds ratios (aORs) were estimated using generalized estimating equations.

The study included 711 cases: 38 conceived within 1-3 months, 111 within 3-6 months, and 562 after >6 months. Major congenital malformations were diagnosed in 70 infants, with no significant difference between groups. Although numerically higher rates of congenital malformations associated with methotrexate embryopathy, preterm birth, and low birth weight were observed in the 1-3 months group, these differences were not statistically significant. Adjusted ORs for congenital malformations were 0.87 (95% confidence interval [CI]: 0.245-3.14) for 1-3 months and 1.01 (95% CI: 0.48-2.13) for 3-6 months, compared to >6 months.

Conception 1-3 and 3-6 months after methotrexate treatment for ectopic pregnancy does not appear to increase the risk of major fetal malformations, or other unfavorable obstetric outcomes. Prospective studies in larger cohorts are warranted.