Severe Adverse Toxic Effects of Low-Dose Methotrexate Treatment on an Ectopic Pregnancy Patient With Methylenetetrahydrofolate Reductase Mutations: A Case Report.

Huan Yu,Wenhui Wang,Kun Wang,Haiyan Liang,Bin Ling

doi:10.3389/fmed.2021.738315

Abstract

Background: Low-dose methylenetetrahydrofolate (LD-MTX) has been widely used for the treatment of the ectopic pregnancy (EP) for many decades, and related severe adverse toxic effects are rare. Current studies have shown that the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene can decrease the MTX clearance, leading to the metabolite accumulation. However, there is a lack of literature report on an MTHFR gene polymorphism associated with adverse toxic effects resulting from the use of LD-MTX in an EP.Case Presentation: We report a rare case of a 38-year-old female who developed persistent fever, grade IV myelosuppression, skin lesions, mucositis, and liver injury after single dose of LDMTX to treat EP. The personalized genetic testing showed that MTHFR TT (677C>T) and MTHFR AA (1298A>C) were detected. Gradually, the symptoms improved after calcium leucovorin (CF) rescue, continuous renal replacement therapy (CRRT), promoting blood system regeneration, and multiple supportive treatments.Conclusion: This is the first report on the serious adverse toxic effects of LD-MTX on an EP patient with MTHFR mutations. We aim to alert obstetricians and gynecologists to this rare condition. The unexpected life-threatening toxicity with LD-MTX should be highly considered and recognized early. In particular, some easily overlooked gastrointestinal, skin, and mucosal symptoms occur earlier than severe myelosuppression. When toxic effects are suspected, detecting the polymorphisms of an MTHFR gene and monitoring MTX concentration in blood could assist us to formulate individualized and active treatments.

Highlights

Methotrexate (MTX) is an antagonist of folic acid, which inhibits dihydrofolate reductase (DHFR) and prevents the proliferation of trophoblasts [1]
LD-MTX can interfere with the DNA synthesis and inhibit proliferation of trophoblasts, preventing embryonic development, and it may lead to absorption [1, 16]
We found that the primary toxic effects of LD-MTX may only be limited to nausea, vomiting, and diarrhea, which are common adverse reactions after chemotherapy and are often ignored

Summary

Introduction

Methotrexate (MTX) is an antagonist of folic acid, which inhibits dihydrofolate reductase (DHFR) and prevents the proliferation of trophoblasts [1]. MTX was first reported to treat ectopic pregnancy (EP) in 1982 [2]. LD-MTX has been used to treat EP for a long time, but only a limited number of its adverse effects have been reported, especially in the single-dose MTX regimen that seems to be a relatively safe treatment [9,10,11,12,13]. Low-dose methylenetetrahydrofolate (LD-MTX) has been widely used for the treatment of the ectopic pregnancy (EP) for many decades, and related severe adverse toxic effects are rare. There is a lack of literature report on an MTHFR gene polymorphism associated with adverse toxic effects resulting from the use of LD-MTX in an EP. The symptoms improved after calcium leucovorin (CF) rescue, continuous renal replacement therapy (CRRT), promoting blood system regeneration, and multiple supportive treatments

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Conclusion