Fruit of the Womb
Fruit of the Womb

Methotrexate - Easy to Use, Easy to Abuse

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I received the two comments below from readers and use this opportunity of their tragic experiences to revisit a concern that I raised about two years ago regarding methotrexate therapy for the presumptive diagnosis of ectopic pregnancy….

Melissa O. said...

I was told I had an ectopic pregnancy and was advised I was in need of a Methotrexate shot. I got it. One week later my hormone level was continuing to rise. Low and behold 4 days later my ultrasound showed I was carrying twins. The Dr.'s had presumed ectopic too early. Getting the shot caused me to loose Twin A and to give birth to a very much underweight 28 weeker. This experience has changed my life forever. My son fought to survive...he continues to today now 13 months old. I would hope anyone who is told they have an ectopic pregnancy would be cautious when it comes to this shot. Yes I agree it helps if your life is in danger due to an ectopic pregnancy. Just take time to ensure there is no doubt that's what it is. My Dr couldn't see the baby so assumed ectopic, however carrying twins like I was you’re not able to see as early as a single pregnancy. My son is paying everyday because of my mistake and doing as one Dr. said make sure you have more than one confirmation, it could cost you a perfectly healthy baby in the end.
Fri Jun 19, 05:45:00 PM 2009

Anonymous said...
Hi can someone help me? My husband and I were trying for a baby and I fell pregnant (good news). I started having a few brown spotting and slight cramping which I was advised by my GP to go to the hospital for a scan. Whilst there I had many tests and the doctors thought it might be ectopic and said he was going to keep me in for a few days to monitor my blood levels. I had a scan but being only five weeks it was hard to say. I was referred to another doctor on the ward and he told me it was ectopic. I trusted his knowledge and he said he needed to give me methotrexate now as it was Friday so the pharmacy would be shut. I was shocked but agreed of course. 3 days later I was told the baby is still alive and is in my womb. My blood levels increased after 3 days and then decreased from 7000 to 6000 on the 7 days. How long will it take to lose my baby as it’s hard to know its alive?
Fri Jul 03, 11:15:00 AM 2009


Ever since methotrexate became popular for treating ectopic pregnancies, I have seen the unfortunate scenario reported by our readers 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.

Because of its documented efficacy in the treatment of malignant trophoblastic cells (choriocarcinoma), MTX has been employed in recent years 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. The ‘absence’ of an intrauterine pregnancy can be misdiagnosed because the pregnancy really is too early, but in at least one of the scenarios above was more likely the result of the inexperience of the individual(s) performing the ultrasound study. This situation can be especially confusing if the pregnancy hormone levels (hCG) appear to be low for the expected gestational age based on last menstrual period (as is often seen in women who ovulate later, and hence conceive later, in their cycles) 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 (rare this early in pregnancy) which 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 advertently 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.

To our readers above, I am SO SORRY for both of you. This is a failing of the medical system and is a growing concern of mine due to the ready accessibility and simplicity of use of methotrexate (and also another drug, misoprostol, that is used in the 'medical evacuation' of the uterus when an inevitable miscarriage is suspected). My feeling is that it should never be used in an asymptomatic or minimally symptomatic patient until either an ectopic pregnancy is seen, no intrauterine pregnancy is documented (by a competent sonographer) at hCG levels where an intrauterine pregnancy should readily be visible, the patient has significant 'risk factors' for an ectopic pregnancy (e.g., previous ectopic, known history of pelvic inflammatory disease or tubal reconstructive surgery) or when there are well-documented abnormalities in the rise of hCG that are highly suggestive of an ectopic pregnancy. My heart goes out to both of you.

Kind regards,
Dr T
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About the Author

Dr. Trofatter is an expert on maternal-fetal medicine.

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