Success of Methotrexate for the Management of Recurrent Compared With Primary Ectopic Pregnancy: A Systematic Review and Meta-analysis.

OBJECTIVE To compare the efficacy of intramuscular (IM) methotrexate in patients with recurrent compared with primary ectopic pregnancy. DATA SOURCES Systematic searches of the MEDLINE, EMBASE, and Scopus databases were conducted in February 2025. METHODS OF STUDY SELECTION This meta-analysis was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. All English-language, full-text studies in which adult patients (18 years of age or older) were treated with IM methotrexate and stratified by their history of a previous ectopic pregnancy were included. Patients with at least one prior ectopic pregnancy, regardless of which fallopian tube was affected and how it was managed, were defined as having recurrent ectopic pregnancy. We excluded studies that did not report patients requiring further treatment, those in which medical management through alternative routes (other than IM) or therapies were studied, and those investigating nontubal ectopic pregnancy or heterotopic pregnancies. TABULATION, INTEGRATION, AND RESULTS Two investigators independently identified studies using the eligibility criteria. The primary outcome was treatment success, characterized by the complete resolution of ectopic pregnancy without the need for further treatment. The efficacy of single-dose and multidose (comprising both two doses and fixed multidose, ie, two or more doses) IM methotrexate regimens was evaluated. Outcomes were reported as relative risk (RR) and 95% CI. From 6,349 search results, 15 observational studies comprising 3,944 patients (502 recurrent, 3,442 primary ectopic pregnancy) were included. Administration of a single dose of IM methotrexate was significantly less successful in patients with recurrent compared with those with primary ectopic pregnancy (RR 0.79, 95% CI, 0.63-1.00, P=.050). However, there was no statistical difference in success for patients receiving multidose treatment (RR 1.14, 95% CI, 0.71-1.84, P=.590). CONCLUSION Current observational data suggest that patients with recurrent ectopic pregnancy should be considered for multidose IM methotrexate to achieve similar rates of success compared with primary ectopic pregnancy. SYSTEMATIC REVIEW REGISTRATION PROSPERO, CRD42025642895.