double-dose methotrexate?

Should Two-Dose Methotrexate Be the Standard of Care for Ectopic Pregnancy?

March 1st, 2019

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By Rebecca H. Allen, MD, MPH

Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI

Dr. Allen reports she receives grant/research support from Bayer and is a consultant for Merck.

SYNOPSIS: In this meta-analysis, the two-dose methotrexate treatment protocol was associated with higher odds of treatment success and a shorter treatment period compared to the single-dose protocol.

SOURCE:Alur-Gupta S, et al. Two-dose versus single-dose of methotrexate for treatment of ectopic pregnancy: A meta-analysis. Am J Obstet Gynecol 2019; Jan 7. pii: S0002-9378(19)30004-3. doi: 10.1016/j.ajog.2019.01.002. [Epub ahead of print].

In this systematic review and meta-analysis, the study population included women with an ectopic pregnancy diagnosed by transvaginal ultrasound, and interventions included single-dose, two-dose, and multi-dose protocols of methotrexate. Alur-Gupta et al searched PubMed, Embase, and the Cochrane Library from inception to July 2018 for randomized, controlled trials for which the full text in English could be accessed. They collected data from each study, including year of study, number of subjects, location of recruitment, mean age of subjects, mean body mass index of subjects, pretreatment hCG, pretreatment adnexal mass diameter, randomization and blinding processes, inclusion and exclusion criteria, description of methotrexate protocols used, definition of outcomes measured including treatment success, length of follow-up, side effects, and surgery for tubal rupture. The primary outcome measured was treatment success (as defined by the individual studies) overall and for the following subgroups: high hCG levels (> 3,000-5,500 mIU/mL) and large adnexal mass (> 2-3.5 cm). Secondary outcomes included side effects (nausea, diarrhea, mucositis, abdominal pain, lab abnormalities), surgery for tubal rupture, and length of follow-up in days.

Seven publications met inclusion criteria for the meta-analysis. None of the studies were performed in the United States. The study size ranged from 70 to 160 patients. Only half the studies reported side effects or length of follow-up, and only five reported rates of surgery for tubal rupture. There were four single-dose vs. two-dose trials and three single-dose vs. multidose trials. For the four single-dose vs. two-dose trials, treatment success was defined variably: hCG < 5 mIU/mL, hCG < 200 mIU/mL, or hCG < 15 mIU/mL within six weeks without surgery or repeat dose. For the primary outcome of treatment success, the two-dose protocol was associated with 1.84 greater odds of success compared to single dose (95% confidence interval [CI], 1.13-3.00). Side effects were 1.53 times more likely in the two-dose compared to the single-dose protocol (95% CI, 1.01-2.30). Odds of surgery for tubal rupture were lower, but not statistically significant (odds ratio [OR], 0.65; 95% CI, 0.26-1.63), and the length of follow up was shorter by 7.9 days (95% CI, 3.5-12.2 days) in the two-dose compared to the single-dose protocol. Women in the high hCG group had 3.23 greater odds of treatment success with two-dose compared to single-dose protocols (95% CI, 1.53-6.84). Similarly, women with larger adnexal masses had more success with the two-dose compared to single-dose regimens (OR, 2.92; 95% CI, 1.23-6.93).
COMMENTARY

Despite advances in detection and treatment, ectopic pregnancy remains a significant cause of maternal morbidity and mortality in the United States.1 The fallopian tubes are the most common site of ectopic pregnancy. Once tubal ectopic pregnancy is diagnosed, treatment includes expectant management (reserved for asymptomatic patients with low initial hCG values), medical management with methotrexate, or surgery (salpingostomy or salpingectomy). Candidates for medical management include women with confirmed or high clinical suspicion for tubal ectopic pregnancy who are hemodynamically stable with an unruptured mass and who do not have absolute contraindications to methotrexate (e.g., intrauterine pregnancy, breastfeeding, clinically significant liver or renal disease, blood dyscrasias, peptic ulcer disease, immunodeficiency, and active pulmonary disease).2 Women initiating methotrexate treatment must agree to close surveillance in case treatment fails and surgical intervention is warranted.

There are single-dose, two-dose, and multidose protocols for methotrexate treatment. The main difference between the single-dose and two-dose protocols are that the two-dose protocol requires administering a second dose of 50 mg/m2 of methotrexate on day 4. Neither regimen requires rescue doses of folinic acid (leucovorin) that are required in the multidose protocols.1 Therefore, both the single-dose and two-dose regimens are simple to follow, and in both protocols, the patient returns on day 4 anyway for an hCG level. Although more exposure to methotrexate increases the risk of side effects, these generally are mild (nausea, vomiting, mucositis) and do not require hospitalization. It is also acknowledged that the single-dose protocol typically requires a second dose of methotrexate in 25% of cases for inadequate declines in hCG values.1 Therefore, the two-dose regimen is seen as a compromise of convenience and efficacy between the single-dose and multidose regimens.

To date, the optimal methotrexate regimen has been debated within the American College of Obstetricians and Gynecologists, which stated that the choice should be guided by the initial hCG level and a discussion with the patient regarding the benefits and risks of each approach.1 Similarly, the American Society for Reproductive Medicine does not favor one approach over another.2 This meta-analysis has several strengths, including stringent criteria for study entry (high-quality randomized, controlled trials only) and the inclusion of more recent studies than past meta-analyses that did not reach the same conclusions.3,4 Alur-Gupta et al made a strong case for using two-dose methotrexate protocols as first-line for the treatment of tubal ectopic pregnancy. Besides the increased success in all women, even in those with higher hCG levels and larger adnexal masses, the shorter treatment duration makes this a compelling argument. Women definitely would appreciate shorter follow-up periods and fewer blood draws. Adopting the two-dose regimen as standard of care also may expand the population that is offered medical management to include women with a higher initial HCG level that typically has been a relative contraindication to methotrexate therapy (> 5,000 mIU/mL).
REFERENCES

Committee on Practice Bulletins-Gynecology. ACOG Practice Bulletin No. 191: Tubal Ectopic Pregnancy. Obstet Gynecol 2018;131:e65-e77.
Practice Committee of American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy: A committee opinion. Fertil Steril 2013;100:638-644.
Yang C, et al. Multiple-dose and double-dose versus single dose administration of methotrexate for the treatment of ectopic pregnancy: A systematic review and meta-analysis. Reprod Biomed Online 2017;34:383-391.
Yuk JS, et al. Systematic review and meta-analysis of single-dose and non-single-dose methotrexate protocols in the treatment of ectopic pregnancy. Int J Gynaecol Obstet 2018;141:295-303.