Two-dose versus single-dose methotrexate for treatment of ectopic pregnancy: a meta-analysis

Am J Obstet Gynecol. 2019 Aug;221(2):95-108.e2. doi: 10.1016/j.ajog.2019.01.002. Epub 2019 Jan 7.


Objective: To compare the treatment success and failure rates, as well as side effects and surgery rates, between methotrexate protocols.

Data sources: PubMed, Embase, and the Cochrane library searched up to July 2018.

Study eligibility criteria: Randomized controlled trials that compared women with ectopic pregnancies receiving the single-dose, two-dose, or multi-dose methotrexate protocols.

Study appraisal and synthesis methods: Odds of treatment success, treatment failure, side effects, and surgery for tubal rupture, as well as length of follow-up until treatment success, were compared using random and fixed effects meta-analysis. Sensitivity analyses compared treatment success in the groups with high human chorionic gonadatropin (hCG) values and a large adnexal mass, as defined by individual studies. The Cochrane Collaboration tool was used to assess risk of bias.

Results: The 2-dose protocol was associated with higher treatment success compared to the single-dose protocol (odds ratio [OR], 1.84; 95% CI, 1.13, 3.00). The 2-dose protocol was more successful in women with high hCG (OR, 3.23; 95% CI, 1.53, 6.84) and in women with a large adnexal mass (OR, 2.93; 95% CI, 1.23, 6.9). The odds of surgery for tubal rupture were lower in the 2-dose protocol (OR, 0.65; 95% CI, 0.26, 1.63), but this was not statistically significant. The length of follow-up was 7.9 days shorter for the 2-dose protocol (95% CI, -12.2, -3.5). The odds of side effects were higher in the 2-dose protocol (OR, 1.53; 95% CI, 1.01, 2.30). Compared to the single-dose protocol, the multi-dose protocol was associated with a nonsignificant reduction in treatment failure (OR, 0.56; 95% CI, 0.28, 1.13) and a higher chance of side effects (OR, 2.10; 95% CI, 1.24, 3.54). The odds of surgery for tubal rupture (OR, 1.62; 95% CI, 0.41, 6.49) and time to follow-up (OR, -1.3; 95% CI, -5.4, 2.7) were similar.

Conclusion: The 2-dose methotrexate protocol is superior to the single-dose protocol for the treatment of ectopic pregnancy in terms of treatment success and time to success. Importantly, these findings hold true in patients thought to be at a lower likelihood of responding to medical management, such as those with higher hCGs and a large adnexal mass.

Keywords: doses; ectopic pregnancy; medical management; methotrexate; protocol; tubal pregnancy.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Systematic Review

MeSH terms

  • Abortifacient Agents, Nonsteroidal / administration & dosage*
  • Chorionic Gonadotropin / blood
  • Dose-Response Relationship, Drug
  • Fallopian Tubes / injuries
  • Fallopian Tubes / surgery
  • Female
  • Humans
  • Methotrexate / administration & dosage*
  • Pregnancy
  • Pregnancy, Ectopic / drug therapy*
  • Randomized Controlled Trials as Topic
  • Rupture / surgery


  • Abortifacient Agents, Nonsteroidal
  • Chorionic Gonadotropin
  • Methotrexate