Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial

Objective Methotrexate is used routinely worldwide for the medical treatment of clinically stable women with a tubal ectopic pregnancy. This is despite the lack of robust evidence to show its superior effectiveness over expectant management. The aim of our multicenter randomized controlled trial was to compare success rates of methotrexate against placebo for the conservative treatment of tubal ectopic pregnancy. Methods This study took place in two early-pregnancy units in the UK between August 2005 and June 2014. Inclusion criteria were clinically stable women with a conclusive ultrasound diagnosis of a tubal ectopic pregnancy, presenting with a low serum beta human chorionic gonadotropin ((ss)-hCG) level of<1500 IU/L. Women were assigned randomly to a single systemic injection of either 50 mg/m(2) methotrexate or placebo. The primary outcome was a binary indicator for success of conservative management, defined as resolution of clinical symptoms and decline of serum (ss)-hCG to<20 IU/L or a negative urine pregnancy test without the need for any additional medical intervention. An intention-to-treat analysis was followed. Results We recruited a total of 80 women, 42 of whom were assigned to methotrexate and 38 to placebo. The arms of the study were matched in terms of age, ethnicity, obstetric history, pregnancy characteristics and serum levels of (ss)-hCG and progesterone. The rates of success were similar for the two study arms: 83% with methotrexate and 76% with placebo. On univariate analysis, this difference was not statistically significant (chi(2) (1 degree of freedom)=0.53; P=0.47). On multivariate logistic regression, the serum level of (ss)-hCG was the only covariate found to be significantly associated with outcome. The odds of failure increased by 0.15% for each unit increase in (ss)-hCG (odds ratio, 1.0015 (95% CI, 1.0002-1.003); P = 0.02). In 14 women presenting with serum (ss)-hCG of 1000-1500 IU/L, the success rate was 33% in those managed expectantly compared with 62% in those receiving methotrexate. This difference was not statistically significant and a larger sample size would be needed to give sufficient power to detect a difference in the subgroup of women with higher (ss)-hCG. In women with successful conservative treatment, there was no significant difference in median (ss)-hCG resolution times between study arms (17.5 (interquartile range (IQR), 14 - 28.0) days (n = 30) in the methotrexate group vs 14 (IQR, 7 - 29.5) days (n = 25) in the placebo group; P = 0.73). Conclusions The results of our study do not support the routine use of methotrexate for the treatment of clinically stable women diagnosed with tubal ectopic pregnancy presenting with low serum (ss)-hCG (<1500 IU/L). Further work is required to identify a subgroup of women with tubal ectopic pregnancy and (ss)-hCG >= 1500 IU/L in whom methotrexate may offer a safe and cost-effective alternative to surgery. Copyright (c) 2016 ISUOG.