Methotrexate in Unruptured Ectopic Pregnancy: Comparing the Single- and Double-dose Treatment

Nazli Navali, Nasim Jabbari Asl, Sanaz Moosavi


Introduction: Ectopic pregnancy (EP) poses a great threat to pregnant women, and in case of misdiagnosis could lead to catastrophic death of the patients. EP patients tend to be treated with surgical or non-surgical treatments. One of the most common therapies in managing EP is Methotrexate (MTX), which the efficacy of its single- and double-dose treatments will be evaluated in this study. Methods: One-hundred and twenty patients with EP, diagnosed in AL-Zahra hospital in Tabriz, Iran, were involved in the study and were divided, randomly, into two groups of 60 (though 4 of the patients in the second group left the study due to discontent, afterwards). For the first group 50 milligrams (mg) of intramuscular (IM) single-dose MTX was prescribed, while for the second group two doses of 50 mg IM MTX were prescribed. The levels of β-hCG were evaluated before the treatment, in the fourth and seventh days, and second and fourth weeks after the treatment. In addition, sonographic findings, clinical symptoms before the treatment, and side effects after treatment were recorded. Results: Success rate for the single-dose group was 85%, while for the double-dose group was 94.6%. However, there was no statistically significant difference between two groups. In addition, there were no significant relations between 2 groups in endometrial thickness, presence of abdominal free fluid and gestational age with the success rate. Regardless, the initial level of β-hCG was an indicator of treatment success rate. In patients with double-dose MTX, required period of time for β-hCG levels to reduce down to zero was significantly lower than the other group. Cut-off point for success rate with single-dose MTX was 3350, with the sensitivity of 88.9% and specificity of 76.5% and for the other group it was 3894.5, with the sensitivity of 66.7% and specificity of 71.7%. Conclusion: No significant difference was observed between single- and double-dose MTX groups in treating EP. The initial levels of β-hCG and mass size were the only factors to predict the treatment success rate. Double-dose regimen lowered β-hCG down to zero earlier than single-dose. Based on Cut-off points, while the initial β-hCG level was below 3350, single-dose treatment was efficient, whereas, between 3350 and 3894.5, double-dose treatment


Ectopic Pregnancy, Single-dose, Double-dose, Methotrexate

Full Text:



Lozeau A-M, Potter B. Diagnosis and management of ectopic pregnancy. Am Fam Physician. 2005;72(9):1707-14.

Leke RJ, Goyaux N, Matsuda T, Thonneau PF. Ectopic pregnancy in Africa: a population-based study. Obstetrics & Gynecology. 2004;103(4):692-7.

Clayton HB, Schieve LA, Peterson HB, Jamieson DJ, Reynolds MA, Wright VC. Ectopic pregnancy risk with assisted reproductive technology procedures. Obstetrics & Gynecology. 2006;107(3):595-604.

Karaer A, Avsar FA, Batioglu S. Risk factors for ectopic pregnancy: A case‐control study. Australian and New Zealand journal of obstetrics and gynaecology. 2006;46(6):521-7.

Furlong L. Pregnancy risk when contraception fails. J Reprod Med. 2002;47(11):881-5.

Saleh HS, Mowafy HE, abd El Hameid AA, Abdelsalam WA, Sherif HE. Double versus single dose methotrexate regimens in management of undisturbed ectopic pregnancy. Critical Care Obstetrics and Gynecology. 2016.

Alkatout I, Honemeyer U, Strauss A, Tinelli A, Malvasi A, Jonat W, et al. Clinical diagnosis and treatment of ectopic pregnancy. Obstetrical & gynecological survey. 2013;68(8):571-81.

Barnhart K, Esposito M, Coutifaris C. An update on the medical treatment of ectopic pregnancy. Obstetrics and gynecology clinics of North America. 2000;27(3):653-67.

Murray H, Baakdah H, Bardell T, Tulandi T. Diagnosis and treatment of ectopic pregnancy. Canadian Medical Association Journal. 2005;173(8):905-12.

Gungorduk K, Asicioglu O, Yildirim G, Gungorduk OC, Besimoglu B, Ark C. Comparison of single-dose and two-dose methotrexate protocols for the treatment of unruptured ectopic pregnancy. Journal of Obstetrics and Gynaecology. 2011;31(4):330-4.

Kasum M, Orešković S, Šimunić V, Ježek D, Tomić V, Tomić J, et al. Treatment of ectopic pregnancy with methotrexate. Acta clinica Croatica. 2012;51(4.):543-8.

Barnhart K, Coutifaris C, Esposito M. The pharmacology of methotrexate. Expert Opinion on pharmacotherapy. 2001;2(3):409-17.

Alleyassin A, Khademi A, Aghahosseini M, Safdarian L, Badenoosh B, Hamed EA. Comparison of success rates in the medical management of ectopic pregnancy with single-dose and multiple-dose administration of methotrexate: a prospective, randomized clinical trial. Fertility and sterility. 2006;85(6):1661-6.

Lipscomb GH, Givens VM, Meyer NL, Bran D. Comparison of multidose and single-dose methotrexate protocols for the treatment of ectopic pregnancy. American journal of obstetrics and gynecology. 2005;192(6):1844-7.

Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a meta-analysis comparing “single dose” and “multidose” regimens. Obstetrics & Gynecology. 2003;101(4):778-84.

Zachariae H. Methotrexate side‐effects. British Journal of Dermatology. 1990;122(s36):127-33.

Medicine PCotASfR. Medical treatment of ectopic pregnancy: a committee opinion. Fertility and sterility. 2013;100(3):638-44.

Taran F-A, Kagan K-O, Hübner M, Hoopmann M, Wallwiener D, Brucker S. The diagnosis and treatment of ectopic pregnancy. Deutsches Ärzteblatt International. 2015;112(41):693.

Stovall TG, Ling FW, Gray LA. Single-dose methotrexate for treatment of ectopic pregnancy. Obstetrics & Gynecology. 1991;77(5):754-7.

Barnhart K, Hummel AC, Sammel MD, Menon S, Jain J, Chakhtoura N. Use of “2-dose” regimen of methotrexate to treat ectopic pregnancy. Fertility and sterility. 2007;87(2):250-6.

Lipscomb GH, McCord ML, Stovall TG, Huff G, Portera SG, Ling FW. Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. New England Journal of Medicine. 1999;341(26):1974-8.

Tas EE, Akcay GFY, Avsar AF. Single-dose methotrexate for the treatment of ectopic pregnancy: Our experience from 2010 to 2015. Pakistan journal of medical sciences. 2017;33(1):13.

Kim J, Jung YM, Lee DY, Jee BC. Pretreatment serum human chorionic gonadotropin cutoff value for medical treatment success with single-dose and multi-dose regimen of methotrexate in tubal ectopic pregnancy. Obstetrics & gynecology science. 2017;60(1):79-86.

Bonin L, Pedreiro C, Moret S, Chene G, Gaucherand P, Lamblin G. Predictive factors for the methotrexate treatment outcome in ectopic pregnancy: A comparative study of 400 cases. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2017;208:23-30.

Jurkovic D, Memtsa M, Sawyer E, Donaldson A, Jamil A, Schramm K, et al. Single‐dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo‐controlled randomized trial. Ultrasound in Obstetrics & Gynecology. 2017;49(2):171-6.

Yang C, Cai J, Geng Y, Gao Y. Multiple-dose and double-dose versus single-dose administration of methotrexate for the treatment of ectopic pregnancy: a systematic review and meta-analysis. Reproductive BioMedicine Online. 2017.

Song T, Kim MK, Kim M-L, Jung YW, Yun BS, Seong SJ. Single-dose versus two-dose administration of methotrexate for the treatment of ectopic pregnancy: a randomized controlled trial. Human Reproduction. 2015;31(2):332-8.

Mirbolouk F, Yousefnezhad A, Ghanbari A. Predicting factors of medical treatment success with single dose methotrexate in tubal ectopic pregnancy: a retrospective study. Iranian journal of reproductive medicine. 2015;13(6):351.

Wu J, Ludlow JP, De Vries B, Black K, Beale P. Single‐dose methotrexate treatment for ectopic pregnancy and pregnancy of unknown location and progesterone as a predictor of success. Australian and New Zealand Journal of Obstetrics and Gynaecology. 2014;54(5):469-74.

Avcioğlu SN, Altinkaya SÖ, Küçük M, Demircan Sezer S, Yüksel H. Predictors of success of different treatment modalities for management of ectopic pregnancy. Obstetrics and gynecology international. 2014;2014.

Skubisz M, Dutton P, Duncan WC, Horne AW, Tong S. Using a decline in serum hCG between days 0–4 to predict ectopic pregnancy treatment success after single-dose methotrexate: a retrospective cohort study. BMC pregnancy and childbirth. 2013;13(1):30.



  • There are currently no refbacks.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

2013-2023 (CC-BY) Australian International Academic Centre PTY.LTD.

Advances in Bioscience and Clinical Medicine