1. UOG Journal Club: February 2017
Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
D Jurkovic, M Memtsa, E Sawyer, ANA Donaldson, A Jamil, K Schramm, Y Sana, M Otify, L Farahanii, N Nunes, G Ambler and JA Ross
Volume 49, Issue 2, Date: February, pages 171–176
Journal Club slides prepared by Dr Joel Naftalin
(UOG Editor for Trainees)

2. Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
Jurkovic et al., UOG 2017
Background
Ectopic pregnancy is a common condition affecting 1-2% of pregnancies worldwide with tubal pregnancies being the most common type.
While fatalities are rare, it has a high financial and emotional burden.
Mainstays of treatment are surgery to remove the pregnancy, and systemic methotrexate for the medical treatment of clinically stable women with a tubal ectopic pregnancy.

3. Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
Jurkovic et al., UOG 2017
Background
Several observational studies have shown a high success rate with expectant management in selected groups.
Expectant management follows the natural history of the disease and, if successful, avoids the risks associated with surgical and medical management.
There are a limited number of studies comparing methotrexate and expectant management in the management of tubal pregnancies.

4. Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
Jurkovic et al., UOG 2017
Objective
To compare success rates of methotrexate against placebo for the conservative management of tubal ectopic pregnancy

5. Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
Jurkovic et al., UOG 2017
Patients and Methods
This was a multicenter randomized controlled trial carried out between August 2005 and June 2014.
All clinically stable women with a conclusive ultrasound diagnosis of a tubal ectopic pregnancy were eligible for the trial.
Inclusion criteria were:
Absence of both an embryonic heart beat and hemoperitoneum on scan
Baseline serum beta human chorionic gonadotropin (β-hCG) <1500IU/L
Normal full blood count and liver and renal function tests
No history of hepatic, renal or pulmonary disease

6. Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
Jurkovic et al., UOG 2017
Study treatment
A computer-generated simple randomization list was used. Recruiters and local pharmacy staff were blinded to the list.
Women allocated to methotrexate treatment received a single gluteal intramuscular injection of 50mg/m2 methotrexate. Women allocated to placebo were given a gluteal intramuscular injection of 0.9% solution of sodium chloride.
All women were given trial medication within 24 hours of their initial visit (day 1)
They attended for follow-up serum β-hCG blood tests on days 4 and 7.

7. Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
Jurkovic et al., UOG 2017
Outcome measures
The primary outcome of the study was defined as resolution of clinical symptoms and decline of serum β-hCG to <20 IU/L or a negative urine pregnancy test without the need for any additional medical intervention.
The treatment was classified as unsuccessful and women were consequently offered surgery if serum β-hCG levels had increased by >15% on two consecutive follow-up visits.
Surgery was also advised for women who developed abdominal pain with evidence of hemoperitoneum on ultrasound.
Secondary outcomes were severe intra-abdominal bleeding requiring blood transfusion, number of emergency laparotomies performed, significant pelvic pain or gastrointestinal side-effects and serum β-hCG resolution times.

8. Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
Jurkovic et al., UOG 2017
Results
A total of 80 women were recruited from two of the three centers. One center failed to recruit any patients.
The two groups were well-matched in terms of age, ethnicity, obstetric history, pregnancy characteristics and serum levels of β-hCG and progesterone.
No women required emergency open surgery and only one woman (in the placebo group) had a blood transfusion.
The diagnosis of a tubal ectopic pregnancy was confirmed in all women who underwent surgery.

9. Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
Jurkovic et al., UOG 2017
Flowchart of participants with ectopic pregnancy randomized to treatment with single dose of methotrexate (MTX) or placebo.

10. Baseline characteristics of study participants
Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
Jurkovic et al., UOG 2017
Baseline characteristics of study participants

11. Primary and secondary outcomes in study partcipants
Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
Jurkovic et al., UOG 2017
Primary and secondary outcomes in study partcipants

12. Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
Jurkovic et al., UOG 2017
Results
The success rate of management according to intention-to-treat was 83% with methotrexate and 76% with placebo (p>0.05).
The success rates according to the actual protocol followed were 89% for methotrexate and 74% for placebo (p>0.05).
β-hCG was the only covariate that retained significance with the odds of failure increasing by 0.15% for each unit increase
The failure rate was significantly higher in the 14 women presenting with a baseline serum β-hCG of IU/L (odds ratio, 6.2 (95% CI, ); P=0.01).
In women with successful conservative management, there was no significant difference in median resolution time of β-hCG between the trial arms (17.5 vs 14 days, p>0.05).

13. Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
Jurkovic et al., UOG 2017
Conclusion
The study does not support the routine use of methotrexate for the treatment of clinically stable women diagnosed with tubal ectopic pregnancies presenting with serum β-hCG <1500IU/L.
Further work is required to assess if methotrexate offers a safe and cost-effective alternative to surgery in clinically stable women diagnosed with tubal ectopic pregnancies presenting with serum β-hCG >1500IU/L.

14. Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
Jurkovic et al., UOG 2017
Limitations
Patients were recruited over a long period of time and one site failed to recruit any patients after the chief investigator left the hospital.
The proportion of patients requiring surgical intervention was lower than the proportion upon which the power calculation was based. This was mainly due to higher than expected spontaneous resolution rates of ectopic pregnancy in the placebo arm.
The majority of eligible women were reluctant to accept that management of their ectopic pregnancy should be decided by chance, with 6/42 women in the methotrexate arm and 3/38 women in the placebo arm declining intervention post-randomization.

15. Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial
Jurkovic et al., UOG 2017
Discussion points
Should expectant management now be the default treatment for clinically stable women with a serum β-hCG <1500IU/L? How can methotrexate be justified in these women?
What are the barriers to wider use of expectant management of tubal pregnancies and how do we overcome them?
Can the results of this study be extrapolated to units that do not routinely offer expectant management of tubal ectopic pregnancies?
Given the time taken to perform this study, how feasible is a study assessing methotrexate vs surgery in clinically stable women diagnosed with ectopic pregnancies presenting with a serum β-hCG >1500IU/L?