Medical management of ectopic pregnancy with single-dose and 2-dose methotrexate protocols: human chorionic gonadotropin trends and patient outcomes

Am J Obstet Gynecol. 2016 Nov;215(5):590.e1-590.e5. doi: 10.1016/j.ajog.2016.06.040. Epub 2016 Jun 28.


Background: Ectopic pregnancy, although rare, is an important cause of female morbidity and mortality and early, effective treatment is critical. Systemic methotrexate has become widely accepted as a safe and effective alternative to surgery in the stable patient. As the number and timing of methotrexate doses differ in the 3 main medical treatment regimens, one might expect trends in serum human chorionic gonadotropin and time to resolution to vary depending on protocol. Furthermore, human chorionic gonadotropin trends and time to resolution may predict ultimate treatment success.

Objective: This study hypothesized that the 2-dose methotrexate protocol would be associated with a faster initial decline in serum human chorionic gonadotropin levels and a shorter time to resolution compared to the single-dose protocol.

Study design: A prospective multicenter cohort study included clinical data from women who received medical management for ectopic pregnancy. Rates of human chorionic gonadotropin change and successful pregnancy resolution were assessed. Propensity score modeling addressed confounding by indication, the potential for differential assignment of patients with better prognosis to the single-dose methotrexate protocol.

Results: In all, 162 ectopic pregnancies were in the final analysis; 114 (70%) were treated with the single-dose methotrexate and 48 (30%) with the 2-dose protocol. Site, race, ethnicity, and reported pain level were associated with differential protocol allocation (P < .001, P = .011, P < .001, and P = .035, respectively). Women had similar initial human chorionic gonadotropin levels in either protocol but the mean rate of decline of human chorionic gonadotropin from day 0 (day of administration of first dose of methotrexate) to day 7 was significantly more rapid in women who received the single-dose protocol compared to those treated with the 2-dose protocol (mean change -31.3% vs -10.4%, P = .037, adjusted for propensity score and site). The 2 protocols had no significant differences in success rate or time to resolution.

Conclusion: In a racially and geographically diverse group of women, the single- and double-dose methotrexate protocols had comparable outcomes. The more rapid human chorionic gonadotropin initial decline in the single-dose group suggested these patients were probably at lower risk for ectopic rupture than those getting the 2-dose protocol. A prospective randomized controlled design is needed to remove confounding by indication.

Keywords: ectopic pregnancy; human chorionic gonadotropin; methotrexate; protocol comparisons.

MeSH terms

  • Abortifacient Agents, Nonsteroidal / administration & dosage*
  • Adult
  • Chorionic Gonadotropin / blood*
  • Cohort Studies
  • Female
  • Humans
  • Linear Models
  • Methotrexate / administration & dosage*
  • Pregnancy
  • Pregnancy, Tubal / blood
  • Pregnancy, Tubal / drug therapy*
  • Prognosis
  • Propensity Score
  • Proportional Hazards Models
  • Prospective Studies
  • Time Factors
  • Young Adult


  • Abortifacient Agents, Nonsteroidal
  • Chorionic Gonadotropin
  • Methotrexate