Abstract

• An ectopic pregnancy results from implantation of a fertilised ovum outside the uterine cavity, usually in a fallopian tube (tubal pregnancy). The clinical course is variable. In some cases, development of the embryo leads to rupture of the fallopian tube, causing massive internal bleeding. This situation is potentially life-threatening for the mother.
   
• Watchful waiting can be considered in certain cases. One treatment option for ectopic pregnancy is surgery, particularly for tubal pregnancy. Injectable methotrexate, a cytotoxic and immunosuppressant drug, is sometimes used.
   
• In 2016, injectable methotrexate became available in France for ectopic pregnancy, through regulated temporary approval. The ectopic pregnancy must be visible on ultrasound, and the woman must have minimal or no symptoms, and a serum hCG concentration below 5000 mIU/ml or 10 000 mIU/ml.
   
• Under these conditions, intramuscular (IM) injection of methotrexate has been compared with surgery in five non-blinded randomised clinical trials, in a total of 371 patients with a tubal ectopic pregnancy.
   
• A meta-analysis of four of these trials showed that a single injection of methotrexate, at a dose of 1 mg/kg, was less effective than surgery at eliminating an ectopic pregnancy, with a success rate of 71% versus 88% (statistically significant difference). When a second injection was given, the success rate rose to 92%, with no statistically significant difference between methotrexate and surgery. No significant differences in subsequent fertility were observed between these treatments. The results of the fifth trial were consistent with this meta-analysis.
   
• A trial in 78 patients compared direct transvaginal injection of methotrexate into the gestational sac versus surgery. The results were similar to those obtained with IM injection.
   
• There has been little evaluation of the adverse effects of brief treatment with injectable methotrexate for ectopic pregnancy. In one of the trials versus surgery, IM methotrexate provoked mouth ulceration, elevated liver enzymes, dry eyes, and neutropenia. Methotrexate also provoked prolonged vaginal bleeding. Pharmacovigilance data show that even brief treatment with injectable methotrexate sometimes provokes severe adverse effects.
   
• Methotrexate is teratogenic. Most of the dose received is eliminated within hours, but a fraction of the dose can persist in the body for several months. It is better to advise women who have been treated with methotrexate for ectopic pregnancy to wait three months before trying to conceive again.
   
•  OFFERS AN ADVANTAGE  In patients with an ectopic pregnancy and no serious manifestations or risk factors for complications, an intramuscular injection of methotrexate, possibly followed by a second injection if the first one fails, has similar efficacy to surgery in eliminating the pregnancy. Direct injection of methotrexate into the gestational sac has been less well evaluated. Even brief treatment with injectable methotrexate can provoke occasionally severe adverse effects, in particular gastrointestinal, haematological and hepatic disorders. Methotrexate's teratogenicity and the fact that a fraction of the dose received can persist in the body for several months justify waiting 3 months before trying to conceive again. It is important to inform patients of the respective advantages and disadvantages of methotrexate and surgery.
  

©Prescrire 1 February 2018

"Injectable methotrexate and ectopic pregnancy. An alternative to surgery but with the risks of a cytotoxic drug, teratogenic in the case of short delay before conception" Prescrire Int 2018; 27 (190): 33-37. (Pdf, subscribers only)

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