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

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.

Low-dose methotrexate-induced renal failure in a patient with ectopic pregnancy: a case report

“…Although the adverse reactions caused by low-dose methotrexate in this case were confused, the patient improved eventually 22 days later, which was similar to the reported case [ 5 ]. Therefore, active treatment after the occurrence of adverse reactions has a relatively good prognosis.…”

“…Very rarely, life-threatening complications have been reported with MTX. To date, only 9 cases of single-dose LD-MTX protocols that induced serious adverse toxic effects on patients with EP have been reported [ 5 ]. In the 10 cases including ours, all the patients had myelosuppression [ 11 – 18 ] most of them had nausea and vomiting, All the 9 patients had fever except our case.…”

“…2 patients had septic shock [ 11 , 14 ], 3 patients had liver injury [ 14 , 15 , 18 ], 2 patients including our case had renal failure [ 18 ] and 3 patients died [ 14 , 15 , 18 ]. In the majority of cases, the patients began to recover in the period of 14–17 days [ 5 ].…”

“…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. To date, eight cases of single-dose LD-MTX protocols that induced serious adverse toxic effects on patients with EP have been reported [ 5 ]. 7 studies also summarize case series, and case reports regarding low-dose methotrexate toxicity in other disease [ 6 ].…”