Low-dose Methotrexate Toxicity in Ectopic Pregnancy: A Case Report and Literature Review

Low-dose methotrexate (LD‑MTX) is widely regarded as a safe and effective fertility‑preserving treatment for selected ectopic pregnancies; however, rare cases of severe, life‑threatening toxicity have been reported. We describe a previously healthy 24‑year‑old woman who developed fulminant systemic toxicity following a single intramuscular dose of 60 mg methotrexate administered for persistent tubal ectopic pregnancy after laparoscopic salpingostomy. Within 72 hours, she presented with progressive mucocutaneous manifestations, including diffuse rash, facial oedema and severe oral ulceration, followed by pancytopenia and acute kidney injury by day 4. Concomitant treatment with long‑acting benzathine penicillin G and subsequent pharmacogenetic testing revealing heterozygous MTHFR C677T and MTRR A66G variants were considered contributory risk factors. Prompt initiation of high‑dose intravenous leucovorin rescue, alkalinised hydration and granulocyte colony‑stimulating factor led to complete haematological recovery by day 14 and normalisation of renal function without the need for glucarpidase or extracorporeal clearance. A review of the literature identified fewer than a dozen similar cases, highlighting consistent early mucocutaneous warning signs and rapid progression to severe myelosuppression. This case underscores that even a single LD‑MTX dose can precipitate severe toxicity when renal clearance is impaired, interacting medications are present and folate‑pathway polymorphisms coexist, and emphasises the critical importance of early symptom recognition, close laboratory monitoring between days 4 and 7, and timely leucovorin rescue.