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Fruit of the Womb

A Complication of Methotrexate Use for Ectopic Pregnancy

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The comment from the reader below was published on one of my posts related to recurrent early pregnancy loss and illustrates one of the risks of methotrexate use in the treatment of ectopic pregnancy...


At Thu Sep 06, 05:52:00 PM 2007, Anonymous said…

Hi. Thank you for answering all these questions. I also had a question regarding Methotrexate. I was injected with a dose of Methotrexate on the 25 of July, 07. I was told my 6 week pregnancy was ectopic and needed to be terminated. One week later I was still pregnant with rising hCG levels. I went to the hospital, had an ultrasound done, and was told I did not have an ectopic pregnancy. I was about 8 weeks along with a living fetus in my uterus. They showed me the fetus with a strong heart beat. Two days later, on Aug 3, I was given a D&C to end the pregnancy. My husband and I would like to try again. We have three boys, I had one miscarriage with my second pregnancy, but the others have been normal. I started my period on September 5. It's pretty heavy. I was wondering if the Methotrexate is out of my system now. Can we try again, or should we wait until after my next period in October? I'm having such a hard time thinking about waiting, but I do know it's important to be careful. I also read taking one baby aspirin a day until conceiving can help the uterus is this true. Thank you.



At Sun Sep 09, 06:21:00 PM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

To Anonymous Sept 6: Ever since methotrexate became popular for treating ectopic pregnancies, I have seen the unfortunate scenario reported by our reader above played out time and time again. Methotrexate (MTX) is an analog of folic acid. It binds tightly to an enzyme called dihydrofolate reductase and when it does so, interferes with the production of tetrahydrofolates. In the end, this interferes with the normal production and repair of DNA by limiting the production of a key nucleotide, thymidine. Other metabolic effects are also known, but the take home message is that MTX can result in lethal damage to cells that are replicating, particularly those that are replicating rapidly, like certain cancer cells.

In the mid-1950’s, Li and colleagues (Proc Exp Biol Med 1956;93:361) demonstrated efficacy of MTX against choriocarcinoma. Choriocarcinioma is a cancer derived from cells of trophoblastic (placental) origin. Although choriocarcinoma only comprises no more than 1% of all gynecologic malignancies, it affects young, reproductive age women and is deadly if not treated. Indeed, before adequate chemotherapy was available, more than 90% of women with metastatic choriocarcinoma died from their disease, usually very rapidly. Thanks to MTX, and other chemotherapeutic agents, most women now survive choriocarcinoma and once remission is achieved, have a very low risk for recurrent disease, ie., they are CURED.

Because of its documented efficacy in the treatment of malignant trophoblastic cells, MTX, in recent years, has been employed as an alternative to surgical therapy in selected cases of ectopic pregnancy (Lipscomb, et al. NEJM 2000;343:1325-29). Ectopic pregnancies, by definition, implant ‘outside the uterus’ with more than 95% occurring in the fallopian tubes and about 2.5% in the cornua of the uterus (where the fallopian tubes enter the uterus). For that reason, they are frequently referred to as ‘tubal pregnancies,’ although they can also occur in the cervix, ovary and intraabdominally. The fallopian tubes cannot restrict the growth of invasive placental tissues, as can the endometrium, and they certainly cannot accommodate a growing embryo beyond a certain point before they rupture and hemorrhage. Indeed, ectopic pregnancies can be quite deadly if not treated appropriately. They are still a major cause of maternal mortality, accounting for 10-15% of all maternal deaths, and they are the leading cause of death in pregnant women in the first trimester. A ruptured ectopic pregnancy is a true medical emergency.

Because of the rising incidence of ectopic pregnancy, the risk (maternal and medical-legal) of not identifying and treating an ectopic pregnancy in a timely fashion, and the widespread acceptance and success of MTX therapy as an alternative to surgical management of an ectopic pregnancy if caught early enough, there has been a coincident increase in the inadvertent use of MTX in unrecognized early intrauterine pregnancies. The usual scenario is one in which the pregnancy is not quite as far along as anticipated and the patient happens to present with complaints of abdominal pain or some spotting and no clear intrauterine pregnancy is identified by ultrasound. This situation can be especially confusing if the pregnancy hormone levels (hCG) appear to be low for the expected gestational age or if a woman has a tender adnexal mass because a hemorrhagic corpus luteum (intraovarian bleeding at the site from which the egg was ‘hatched’) or torsion of an adnexal mass might be very difficult to differentiate from an ectopic pregnancy.

Since MTX is a category X drug, known to be teratogenic in humans, it is important to ascertain the presence of an ectopic pregnancy rather than simply to use it empirically. Unfortunately, its use in advertantly with an intrauterine pregnancy is most likely to occur during the time of neural tube and very early cardiac development, both of which rely on folate-dependent pathways. Various algorithms are in place that employ ultrasound imaging, quantitative hCG levels, and progesterone levels to differentiate abnormal from potentially normal pregnancies and these protocols can be useful in minimizing the chance of the inadvertent use of MTX and also in directing its use when appropriate for the management of an ectopic pregnancy. Perhaps the greatest risk of ectopic pregnancy is not suspecting that one could be present. Patients who are adequately counseled and followed closely are much less likely to end up in emergency situations.

Anyway, to finish the response to our reader’s questions, because the ‘half-life’ of MTX is measured in hours, and you received a very short course of the drug, you are probably 'safe' now to pursue another pregnancy from that standpoint. Whenever a D&C is perfomed, however, we often recommend waiting 3-4 months before attempting another pregnancy so that the inflammation in the uterus can die down and the endometrium fully reconstitute to improve the prospects for successful and normal implantation of another pregnancy. So, I would suggest waiting until after your next period and in the interim, starting supplemental folic acid 4 mg/day as well as a prenatal vitamin to reduce your risk even more. Before you start a baby aspirin, it is probably a good idea to discuss that with your doctor. Start all of this BEFORE you try to get pregnant and continue through the first trimester. Good luck next time and let me know how things turn out. Thanks again for reading and for a great question.
Dr T
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