Medical Management of Interstitial Pregnancy With Methotrexate: A Systematic Review and Meta‐Analysis of Case Reports and Case Series

ABSTRACT Aim Interstitial pregnancy (IP) is a rare, life‐threatening ectopic pregnancy, accounting for 2%–4% of cases, with high rupture and mortality risk. Methotrexate (MTX) offers a fertility‐preserving alternative to surgery, but evidence on its efficacy and safety remains limited. Methods PubMed, Scopus, and Google Scholar were searched from 1990 to September 2025 for English‐language case reports and series on IP managed with MTX. Primary outcome was treatment success rate. Subgroup analyses evaluated protocol, administration route, dosing, folic acid use, and baseline β‐hCG levels. Results A total of 124 patients from 77 case reports and series were included. The mean age was 31.9 ± 6.0 years, with a mean gestational age of 7.1 ± 1.5 weeks. Vaginal bleeding (44.7%) and asymptomatic presentation (38.6%) were most common. Pooled treatment failure with MTX was 31% (95% CI: 0.26–0.36), and complications occurred in 37% (95% CI: 0.32–0.42). Local administration showed a lower failure rate compared to systemic (20% vs. 34%). A 1 mg/kg regimen had fewer failures compared to 50 mg/m 2 (23% vs. 33%). Patients with baseline β‐hCG > 5000 IU/L had higher failure (34% vs. 24%) and complication rates (42% vs. 26%) than those with lower levels. Folic acid use, single versus multiple doses, and combined systemic/local routes did not significantly affect outcomes. Most adverse events were minor; rupture occurred in 6.5% of cases. Conclusions MTX is an effective, safe, fertility‐sparing option for IP, achieving high resolution rates across protocols. Local administration and 1 mg/kg regimens may reduce failure. Multicenter studies are needed for standardized guidelines.