Cohen et al present a welcome study of a large cohort (409) treated with methotrexate (MTX) for ectopic pregnancy (EP). They worry that the success rates were lower than previously thought. However, their success rate is a quite high 88% for human chorionic gonadotrophin (β-hCG) level 1500-2000 IU/mL and a reasonably good 65.5% for β-hCG level >4500 IU/mL, thus supporting MTX as an appropriate/preferred treatment in early nonresolving EP (in agreement with several other studies). Remarkably, 62% of women eligible for β-hCG follow-up had 15% daily decline of β-hCG and did not need treatment. This higher percentage may be due to different admixture true EPs and pregnancies of unknown location. National Health Service Hospitals in the UK avoid transvaginal scans before 6 weeks unless there is significant pain, and hence may have fewer pregnancies of unknown location.

A recent randomized controlled trial is sometimes quoted as evidence that expectant management is as effective as MTX in EP with plateauing β-hCG. It recruited a very small number of women (39 for MTX and 32 for expectant) with fairly low β-hCG levels (median ± SD of 535 ± 500 IU/mL and 708 ± 376 IU/mL, respectively) at randomization (day 4). At least in some women the β-hCG may have been already falling because the inclusion criteria were <50% rise or fall (plateauing) between day 0-4. The success rate with a single dose of MTX was 76% (relative risk, 1.3; 95% confidence interval, 0.9–1.8) but increased to 98% with a second dose. The success with expectant management was 59% but it may have been even lower where β-hCG was rising rather than falling. Clearly, simply a larger number of subjects would push the 95% confidence interval well to the right of 1.0. Thus, this randomized controlled trial actually seems to confirm significantly better success rate with MTX (especially if β-hCG is not already declining and certainly with 2 doses).

Recently, concerns have arisen regarding inadvertent administration of MTX to viable intrauterine pregnancy causing major fetal malformations and multimillion dollar compensation claims. Contrary to belief, strict protocols should prevent these mishaps. The protocol introduced by the author over the last 10 years requires at least 3 β-hCG results showing suboptimal rise (<62% every 48 hours) and absence of intrauterine pregnancy on transvaginal ultrasound scan. MTX should not be administered based on 1 or 2 β-hCG results (even when >1500 IU/mL) because of about 10% false-positive and false-negative results and rarely very early multiple pregnancy. On the other hand, increased liberal expectant management may risk excessively prolonged follow-ups, more tubal ruptures (with no reliable way to predict), and chronic EPs.