Side Effects Side effects of methotrexate therapy are dose and frequency dependent. The most commonly reported side effects are the gastrointestinal symptoms of nausea, vomiting, stomatitis, and abdominal pain. Because of these potential effects, women are cautioned against using alcohol and nonsteroidal anti-inﬂammatory medications while being treated with methotrexate (190). Other side effects include bone marrow suppression, hemorrhagic enteritis, alopecia, dermatitis, elevated liver enzyme levels, and pneumonitis (204). These side effects are usually mild and self-limited; few life-threatening side effects are reported with methotrexate treatment for ectopic pregnancy. The risk of these side effects does not appear to differ between single-dose and multidose regimens when adjusting for starting level of β-hCG at initiation of treatment. The frequency of reported side effects ranges from 30% to 40% (194). For those patients on prolonged therapy, leucovorin can reduce the incidence of these side effects and is included in the “multidose” regimen. Long-term follow-up of women treated with methotrexate for gestational trophoblastic disease shows no increase in congenital malformations, spontaneous abortions, or tumors recurring after chemotherapy (205). Treatment of ectopic pregnancy differs from that of gestational trophoblastic disease in that a smaller total dose of methotrexate is required and shorter treatment duration is used.
Although surgical management of ectopic pregnancy remains the mainstay of treatment worldwide, methotrexate treatment is appropriate in those patients who meet the treatment criteria previously detailed.
Reproductive Outcome Reproductive function after methotrexate treatment can be assessed on the basis of repeat ectopic pregnancy rates, tubal patency, and pregnancy outcome. The risk of subsequent ectopic pregnancy is approximately 10% following either methotrexate or salpingostomy (52,53). The tubal patency rates are reported to be higher than 80% in those patients treated with either single-dose or multidose regimens with no difference in rates compared with women treated with salpingostomy (52,53). A randomized trial comparing methotrexate to laparoscopic salpingostomy showed no difference in tubal patency rates among the two groups, although in this trial patency rates were lower than previously reported at 66% in the salpingostomy group (206).
Subsequent spontaneous intrauterine pregnancy rates are similar between those women treated with methotrexate versus salpingostomy, with rates ranging from 36% to 64% (207,208). Comparison of laparoscopically treated patients with methotrexate-treated patients indicates that the two methods have similar reproductive outcomes.
Salpingocentesis is a technique in which agents such as KCl, methotrexate, prostaglandins, and hyperosmolar glucose are injected into the ectopic pregnancy transvaginally using ultrasonographic guidance, transcervical tubal cannulization, or laparoscopy. Agents injected under ultrasonographic guidance included methotrexate, KCl, combined methotrexate and KCl, and prostaglandin E2 (162,209–215). The potential advantages of salpingocentesis include a onetime injection with the potential avoidance of systemic side effects. Reproductive function after this form of treatment was not reported. Because of the limited experience, this treatment cannot be recommended until there is further study.