How soon after methotrexate treatment for ectopic pregnancy can in vitro fertilization with a froze

Fråga: How soon after methotrexate treatment for ectopic pregnancy can in vitro fertilization with a frozen embryo be performed? The question concerns a woman who had two single 75 mg methotrexate doses one week apart, due to ectopic pregnancy after in vitro fertilization. There are frozen embryos available for further treatment.

Sammanfattning: There are severel studies reporting successful IVF treatment within 3-6 months after methotrexate treatment for ectopic pregnancy. However, there is no solid information to be found to either support or contra-indicate IVF treatment sooner than 3 months after methotrexate treatment. It seems prudent to wait at least one month after methotrexate treatment, until the next embryo implantation is tried.

Svar: Methotrexate is an inhibitor of dihydrofolic acid reductase and prevents the formation of active tetrahydrofolate from folic acid. Tetrahydrofolate is necessary for the synthesis of thymidylate, an essential component of DNA. Methotrexate has mutagenic properties and is contraindicated during pregnancy. The manufacturer also advices against planning for pregnancy within 3-6 months after treatment of either parent (1). This recommendation seems to be based mainly on the length of the spermatogenetic cycle and thus refers to male exposure to methotrexate prior to conception (2). However, there is also some concern regarding the intracellular pharmacokinetics of methotrexate. Methotrexate has a half-life in plasma between 3-15 hours. The substance usually becomes undetectable in plasma within 24 hours after a given dose. However, some amount of methotrexate may also recide intracellularly, in a polyglutamate form, for a considerable time. The time for methotrexate polyglutamate to become undetectable in red blood cells, after stopping antirheumatic treatment, has been reported to be up to ten weeks (3). For women treated with metothrexate at any time before conception, the current recommendation is to perform a fetal chromosome analysis (4).

A literature search revealed four retrospective studies concerning IVF after methotrexate treatment. The first study included 14 women who had been treated with a single 1mg/kg dose of methotrexate for ectopic pregnancy after IVF. The main outcome was to study whether the ovarian reserve had been compromised. No differences were seen comparing the pre- and post methotrexate treatment cycles with respect to levels of anti-Müllarian hormone, number of oocytes retrieved or number of embryos obtained. The mean time between cycles was 7.5 months, with no range given (5).

Similar results are reported from a very similar study, also including 14 women, were the mean time between methotrexate treatment and the subsequent IVF cycle was 5.7 months, range 3.5 12 months (6).

In the third study, no differences in sonographic characteristics of the endometrium and follicles during IVF cycles before and after methotrexate treatment were detected in eleven women. The median time between cycles was 6 months (range 5-15) months (7).

In the largest study, including 35 women, a lower oocyte retrieval rate was noticed in IVF cycles taking place within 6 months after methotrexate treatment, compared with those taking place later on (8).

In a study on unassisted pregnancy after methotrexate treatment, the outcome of 45 pregnancies, occurring within 6 (mean, SD 3.6 +/- 1.7) months after methotrexate treatment of ectopic pregnancy, was compared with the outcome of 80 pregnancies occurring later the 6 months (mean 24 months) after methotrexate treatment. No significant differences were seen in the rate of abortions, pre-term births or malformations (9).

In the present case, there are two concerns: is the probability of establishing a new pregnancy reduced by the recent methotrexate exposure to the mother, and is there a risk of malformations in the fetus, should a new pregnancy occur within three months? None of the above studies are clearly relevant for either of the two questions. Theoretically, there could be a risk of reduced endometrial thickness in the menstrual cycle following directly after methotrexate treatment, which could possibly affect the probability of pregnancy. As for the risk of malformations in an embryo, safely stored in a freezer at the time of maternal drug exposure, this must be considered to be very low. It does, however, seem prudent to wait at least one month after methotrexate treatment, until the next embryo implantation is tried.