A systematic review and meta-analysis «Bhat S, Bhat S, Sircar S. Success of Methotrexate for the Management of Recurrent Compared With Primary Ectopic Pregnancy: A Systematic Review and Meta-analysis. Obstet Gynecol 2025;(): »3 assessed the efficacy of intramuscular methotrexate (MTX) in patients with recurrent compared with primary ectopic pregnancy. 15 observational studies with 3 944 patients (502 recurrent, 3 442 primary ectopic pregnancy) were included. Single dose MTX was significantly less successful in patients with recurrent compared with those with primary ectopic pregnancy (RR 0.79, 95% CI 0.63 to 1.00). However, there was no statistical difference in success for patients receiving multidose treatment (RR 1.14, 95% CI, 0.71 to 1.84).
A retrospective cohort study «Fu L, Liu X, Tian Z, et al. Risk factors for methotrexate treatment failure in tubal ectopic pregnancy: a retrospective cohort study. BMC Pregnancy Childbirth 2024;24(1):884. »4 included a total of 359 patients, with 268 (74.7%) succeeding with MTX and 91 (25.3%) required surgery. Specifically, 282 patients (78.6%) received 1-dose MTX, whereas 77 (21.4%) received 2-dose MTX. Gravidity, previous ectopic pregnancy, gestational age, pretreatment β-human chorionic gonadotropin (β-hCG) level, number of MTX treatments, and presence of a visible yolk sac in ultrasound were significant predictors. Higher gravidity (OR 1.25, 95% CI 1.01 to 1.54) and elevated pretreatment β-hCG levels (OR 1.00, 95% CI 1.0004 to 1.0008) were independent risk factors. Number of MTX treatments was a significant protective factor (OR 0.44, 95% CI 0.22 to 0.90).
A randomized controlled trial «Song T, Kim MK, Kim ML et al. Single-dose versus two-dose administration of methotrexate for the treatment of ectopic pregnancy: a randomized controlled trial. Hum Reprod 2016;31(2):332-8. »2 assessed the efficacy of single-dose versus two-dose administration of methotrexate for ectopic pregnancy. 92 women were randomly assigned to follow either the single-dose or two-dose protocol. The success rates between the single-dose and two-dose groups did not show a significant difference (82.6 versus 87.0%; RR 0.95; 95% CI 0.80 to 1.13). However, the success rate in a subgroup of participants with a pretreatment hCG level over 5000 mIU/ml appeared to be higher in the two-dose group than in the single-dose group (80.0 versus 58.8%), although the difference was not statistically significant. No significant differences in methotrexate-associated side effects, cost or treatment satisfaction were observed between the groups.
A multicentre RCT «van Mello NM, Mol F, Verhoeve HR et al. Methotrexate or expectant management in women with an ectopic pregnancy or pregnancy of unknown location and low serum hCG concentrations? A randomized comparis»1 included 73 women who were assigned to systemic single dose methotrexate (MTX) treatment or expectant management. Serum hCG concentration was under 2000 IU/l. There was no difference in primary treatment success rate of single-dose MTX versus expectant management, 31/41 (76%) and 19/32 (59%), respectively (RR 1.3 95% CI 0.9 to 1.8). Nine women (22%) needed additional MTX injections, compared with 9 women (28%) in whom systemic MTX was administered after initial expectant management (RR 0.8; 95% CI 0.4 to 1.7). One woman (2%) from the MTX group underwent surgery compared with 4 women (13%) in the expectant management group (RR 0.2; 95% CI 0.02 to 1.7),
Comment: The quality of evidence is downgraded by study limitations, and partially by imprecise results (limited study size for each comparison).