Sunday, April 16, 2017

Methotrexate, Obesity, and Ectopic Pregnancy

Obstetric emergencies can be challenging to many pharmacists given the critical nature of these diseases and the need for immediate recall of medication information ranging from teratogenicity to second/third line agents in light of drug shortages.(1-4) Ectopic pregnancy is one of those scenarios where advanced knowledge and comprehension of the medical management is essential for pharmacists working in emergency departments. This, in large part, is as a result of the frequent use of methotrexate for this indication and the instilled fear of methotrexate from pharmacy school. Despite all of the safety measures deployed to reduce the likelihood of selecting the incorrect dosing (since there are many variations) confusion can still occur. However, given the worsening obesity epidemic in the United States, whether or not to adjust the dosing of methotrexate (often based on body surface area {BSA}) can further complicate the use of this drug.

Early application of methotrexate to management of ectopic pregnancy used moderate doses of 1mg/kg IM on days 0, 1, 3, 5, 7 with leucovorin rescue.(5,6)  While this regimen was clinically successful in reducing hCG level by 15% over two days in 92.7% of patients, several simpler single or two-dose regimens have found to be similarly effective and have replaced this multidose option.(6)  At many institutions, methotrexate is now dosed at 50 mg per meter squared on day 0 and hCG level is assessed on day 4, with the option for a one-time repeat dose of methotrexate if hCG level have not declined by 15% between days 4 and 7.

Contraindications and relative contraindications in ectopic pregnancy

Contraindication to methotrexate
High risk of treatment failure or relative contraindications
Allergy to methotrexate
Hemodynamically unstable/Ruptured ectopic pregnancy
Intrauterine pregnancy
Active pulmonary disease
Renal/Liver disease
Preexisting blood dyscrasia
Peptic ulcer disease
Unable to follow up
hGG > 5000 nIU/,L
Large mass > 3.5 cm
Embryonic cardiac activity present
IUP has not been ruled out

However, in obese and morbidly obese patients, dosing based on BSA may lead to underdosing (not to mention inadvertent subcutaneous administration and altered absorption characteristics), treatment failure and potential complications or surgery.(7) On the flip side, methotrexate can cause dose-dependent toxicities including stomatitis, esophagitis, kidney failure, myelosuppression, hepatitis, and central nervous system dysfunction.(8) Therefore, it is necessary to limit the exposure of patients to this drug to the minimum necessary to achieve the desired clinical outcome.

Unfortunately, there is no recommendation from ACOG on how to approach methotrexate dosing in obese patients, and until recently there was no evidence of whether dose adjustments or capping in safety or efficacy.

In this recent study from Detroit, Hoyos et al. conducted a retrospective cohort study of patients diagnosed with tubal ectopic pregnancy who underwent medical management with methotrexate dosed at 50 mg per meter squared, but with a maximum dose of 100 mg, over a 3 year period.(9)

Patients were included if the ectopic pregnancy was located in the fallopian tube, had a BMI recorded, were hemodynamically stable, consented to methotrexate therapy, and had at least one beta-hCG follow up level drawn. They excluded patients whose initial beta-hCG was less than 1000 mIU/mL, did not have beta-hCG follow up or were not treated with single-dose methotrexate.

Patients who met the study inclusion criteria were divided into two groups based on their BMI; > 40 kg per meter squared or < 40 kg per meter squared. Analyses were also planned for patients divided into the following groups: presence of embryonic heart tones, maximum diameter of ectopic size (<35 mm="" vs=""> 35 mm) and beta-hCG levels before methotrexate (< 5000 mIU/mL vs > 5000 mIU/mL).

The main outcome measures were as follows: a decrease in serum beta-hCG of at least 80% following methotrexate, need for > 2 doses of methotrexate, surgery despite medical management, a combined variable of either surgery or the need for additional methotrexate as defined as a decrease in serum beta-hCG of at least 80% following methotrexate. 

During the study period, 290 patients were identified, but 137 (47.2%) were excluded due to hCG levels less than 1000 mIU/mL. Of the remaining 151 patients, 89.4%(135/151) were non-morbidly obese (BMI < 40kg/m2), leaving only 10.6% (16/151) in the morbidly obese arm.

With regards to the study outcomes, morbidly obese patients (BMI > 40 kg/m2) were significantly more likely (31.3%, 5/16) to require at least 2 doses of methotrexate compared to non-morbidly obese patients (8.2%, 11/134, OR 5.1 95% CI 1.5-17.3, p =0.015). However, there were no statistically significant differences in the proportion of patients requiring surgery despite medical management, achieving a decrease in serum beta-hCG of at least 80% following methotrexate or a combined variable of either surgery or the need for additional methotrexate.

The authors concluded that this method of dose capping led to more patients requiring additional methotrexate doses, but concede that there is insufficient data to make any recommendations and adequately powered randomized studies are needed.

Given the nature of the design of this study, its inherent limitations, lack of safety data for both higher doses of methotrexate or clinical sequelae of repeated doses vs underexposure, this study does little more than add confusion. As is seems currently, there is another medication safety paradox emerging: methotrexate dosing can continue to increase with increasing BMI, with unknown consequences - or - methotrexate dosing can be empirically/arbitrarily capped with unknown consequences.

Given the awareness of methotrexate from a toxicologic perspective can shed some light on this paradox. Consider a patient with a BSA of 2.25 m2 - (roughly 62” and 130kg). Based on a 50 mg/m2 dose, this patient would receive 112.5 mg IM x 1.

  • Absorption: while the absorption from IM tissue is desired, there is no guarantee that there will be sufficient needle penetration beyond subcutaneous tissue. The clinical ramifications of this are unknown. 
  • Distribution/elimination: Methotrexate distribution (0.6-0.9% L/kg) does not appear to be affected by obesity based on pharmacokinetic data from a single case report(10). But, the third phase of methotrexate elimination (redistribution from tissues), patients could be exposed to methotrexate for longer periods of time, possibly mimicking the common error of daily vs weekly oral methotrexate. 
  • Risk reduction: So you give a little more methotrexate, then avoid other drugs that will increase risk of nephrotoxicity from methotrexate (ex., NSAIDs, aminoglycosides, salicylates and piperacillin).(8) 
  • Consider the dose: Capping the dose at 100 mg or giving 112.5 mg comes nowhere close to higher doses use for cancer (upwards of 1-10g per m2). So perhaps this concern is really not a concern at all.  


1 - Gynceologists ACoG. ACOG Practice Bulletin No. 94: Medical management of ectopic pregnancy. Obstet Gynecol 2008; 111(6):1479-85.
2 - Barnhart KT, et al. Clinical practice. Ectopic pregnancy. N Engl J Med 2009;361(4):379-87.
3 - Seeber BE, Barnhart KT. Suspected ectopic pregnancy [published correction appears in Obstet Gynecol. 2006;107(4):955]. Obstet Gynecol 2006;107(2 pt 1):399-413.
4 - Lipscomb GH, et al. Medical management of ectopic pregnancy. Clin Obstet Gynecol 2012;55(2):424-32.
5 - Barnhart KT, et al. The medical management of ectopic pregnancy: a meta-analysis comparing single dose and multidose regimens. Obstet Gynecol 2003;101(4):778-784.
6 - Bachman EA, et al. Medical Management of Ectopic Pregnancy: A Comparison of Regimens. Clin Obstet Gynecol 2012 Jun; 55(2): 440-447.
7 - Pai MP, et al. Drug dosing based on weight and body surface area: mathematical assumptions and limitations in obese adults. Pharmacotherapy 2012;32(9):856-68.
8 - Wang RY. Wang R.Y. Wang, Richard Y. Chemotherapeutics: Methotrexate. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. Hoffman R.S., Howland M, Lewin N.A., Nelson L.S., Goldfrank L.R. Eds. Robert S. Hoffman, et al.eds. Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015. Accessed April 15, 2017.
9 - Hoyos LR, et al. Morbid obesity and outcome of ectopic pregnancy following capped single dose regimen methotrexate. Arch Gynecol Obstet 2017; 295:375-81.
10 - Flemming R, et al. Disposition of high-dose methotrexate in obese cancer patient. Cancer 1991;68:1247-50.

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