Predictors of Methotrexate Failure and Tubal Rupture in Patients With Tubal Ectopic Pregnancy: A Retrospective Cohort...

Tubal ectopic pregnancy remains a potentially life-threatening condition despite advances in early diagnosis and management. Although methotrexate (MTX) is widely used in clinically stable patients, treatment escalation and tubal rupture may still occur. This study primarily aimed to evaluate MTX treatment outcomes and identify pretreatment clinical, laboratory, and ultrasonographic factors associated with tubal rupture during MTX therapy in tubal ectopic pregnancy.

This single-center retrospective cohort study included women with confirmed tubal ectopic pregnancy managed between October 2023 and June 2025. According to the pre-established institutional protocol, patients received either primary surgical treatment or first-line systemic methotrexate treatment. Only cases with tubal localization confirmed by follow-up transvaginal ultrasonography and/or intraoperative findings were included. MTX was administered using a single-dose regimen (50 mg/m²), with a second dose given in clinically stable patients when indicated. Requirement for a second MTX dose was considered treatment escalation rather than treatment failure; MTX failure was defined as the need for surgical intervention. Demographic, clinical, laboratory, and ultrasonographic variables were analysed. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive value of baseline β-human chorionic gonadotropin (β-hCG) levels and ectopic mass size for tubal rupture during MTX therapy.

A total of 194 women were included; 54 (27.8%) underwent primary surgery and 140 (72.2%) received MTX as initial treatment. Among MTX-treated patients, single-dose MTX was successful in 94 patients (67.1%), 24 (17.1%) required a second dose, and tubal rupture requiring surgical intervention occurred in 22 (15.7%). Patients who developed rupture had significantly higher baseline, day-4, and day-7 β-hCG levels, larger ectopic mass size, and a markedly higher frequency of free intraperitoneal fluid compared with those successfully treated with MTX (all p < 0.05). The decline in β-hCG levels between days 4 and 7 was significantly lower in patients requiring treatment escalation or developing rupture (p < 0.001). Although fetal cardiac activity was numerically more frequent in the MTX-related rupture subgroup, this difference was not statistically significant after analysis with the Fisher-Freeman-Halton exact test. Gestational age at presentation was significantly greater in patients who later developed MTX-related rupture than in those who underwent primary surgery (p = 0.009). Receiver operating characteristic analysis demonstrated excellent discriminative performance for baseline β-hCG (area under the curve [AUC] = 0.869; 95% confidence interval [CI], 0.769-0.970; p < 0.001; cut-off = 1670 mIU/mL; sensitivity 95.2%, specificity 77.1%) and good discriminative performance for ectopic mass size (AUC = 0.766; 95% CI, 0.632-0.900; p = 0.001; cut-off = 30 mm; sensitivity 68.4%, specificity 87.7%).

Baseline β-hCG level and ectopic mass size are clinically useful pretreatment predictors of tubal rupture during MTX therapy in tubal ectopic pregnancy. Incorporating these variables into pretreatment risk stratification may improve patient selection, counselling, and safety during medical management.