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

Jia-Chen Cheng; Wen-Yang Xie; Xue Wu; Pu Li

doi:doi:10.11648/j.jgo.20261401.13

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| Peer-Reviewed

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

Jia-Chen Cheng

, Wen-Yang Xie

, Xue Wu

, Pu Li^*

Published in Journal of Gynecology and Obstetrics (Volume 14, Issue 1)

Received: 11 December 2025 Accepted: 22 December 2025 Published: 30 January 2026

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Abstract

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.

Published in	Journal of Gynecology and Obstetrics (Volume 14, Issue 1)
DOI	10.11648/j.jgo.20261401.13
Page(s)	30-36
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2026. Published by Science Publishing Group

Keywords

Methotrexate Toxicity, Ectopic Pregnancy, Pharmacogenetics, MTHFR, OAT3, Leucovorin Rescue

References

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APA Style

Cheng, J., Xie, W., Wu, X., Li, P. (2026). Low-dose Methotrexate Toxicity in Ectopic Pregnancy: A Case Report and Literature Review. Journal of Gynecology and Obstetrics, 14(1), 30-36. https://doi.org/10.11648/j.jgo.20261401.13

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ACS Style

Cheng, J.; Xie, W.; Wu, X.; Li, P. Low-dose Methotrexate Toxicity in Ectopic Pregnancy: A Case Report and Literature Review. J. Gynecol. Obstet. 2026, 14(1), 30-36. doi: 10.11648/j.jgo.20261401.13

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AMA Style

Cheng J, Xie W, Wu X, Li P. Low-dose Methotrexate Toxicity in Ectopic Pregnancy: A Case Report and Literature Review. J Gynecol Obstet. 2026;14(1):30-36. doi: 10.11648/j.jgo.20261401.13

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@article{10.11648/j.jgo.20261401.13,
  author = {Jia-Chen Cheng and Wen-Yang Xie and Xue Wu and Pu Li},
  title = {Low-dose Methotrexate Toxicity in Ectopic Pregnancy: 
A Case Report and Literature Review},
  journal = {Journal of Gynecology and Obstetrics},
  volume = {14},
  number = {1},
  pages = {30-36},
  doi = {10.11648/j.jgo.20261401.13},
  url = {https://doi.org/10.11648/j.jgo.20261401.13},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.jgo.20261401.13},
  abstract = {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.},
 year = {2026}
}

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TY  - JOUR
T1  - Low-dose Methotrexate Toxicity in Ectopic Pregnancy: 
A Case Report and Literature Review
AU  - Jia-Chen Cheng
AU  - Wen-Yang Xie
AU  - Xue Wu
AU  - Pu Li
Y1  - 2026/01/30
PY  - 2026
N1  - https://doi.org/10.11648/j.jgo.20261401.13
DO  - 10.11648/j.jgo.20261401.13
T2  - Journal of Gynecology and Obstetrics
JF  - Journal of Gynecology and Obstetrics
JO  - Journal of Gynecology and Obstetrics
SP  - 30
EP  - 36
PB  - Science Publishing Group
SN  - 2376-7820
UR  - https://doi.org/10.11648/j.jgo.20261401.13
AB  - 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.
VL  - 14
IS  - 1
ER  -

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Author Information

Jia-Chen Cheng

The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

http://orcid.org/0009-0009-6407-7705
Wen-Yang Xie

The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

http://orcid.org/0009-0000-0548-951X
Xue Wu

The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

http://orcid.org/0000-0002-9544-1815
Pu Li

The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

Contact Email

http://orcid.org/0009-0000-1659-5553

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APA Style

Cheng, J., Xie, W., Wu, X., Li, P. (2026). Low-dose Methotrexate Toxicity in Ectopic Pregnancy: A Case Report and Literature Review. Journal of Gynecology and Obstetrics, 14(1), 30-36. https://doi.org/10.11648/j.jgo.20261401.13

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ACS Style

Cheng, J.; Xie, W.; Wu, X.; Li, P. Low-dose Methotrexate Toxicity in Ectopic Pregnancy: A Case Report and Literature Review. J. Gynecol. Obstet. 2026, 14(1), 30-36. doi: 10.11648/j.jgo.20261401.13

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AMA Style

Cheng J, Xie W, Wu X, Li P. Low-dose Methotrexate Toxicity in Ectopic Pregnancy: A Case Report and Literature Review. J Gynecol Obstet. 2026;14(1):30-36. doi: 10.11648/j.jgo.20261401.13

Copy | Download

@article{10.11648/j.jgo.20261401.13,
  author = {Jia-Chen Cheng and Wen-Yang Xie and Xue Wu and Pu Li},
  title = {Low-dose Methotrexate Toxicity in Ectopic Pregnancy: 
A Case Report and Literature Review},
  journal = {Journal of Gynecology and Obstetrics},
  volume = {14},
  number = {1},
  pages = {30-36},
  doi = {10.11648/j.jgo.20261401.13},
  url = {https://doi.org/10.11648/j.jgo.20261401.13},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.jgo.20261401.13},
  abstract = {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.},
 year = {2026}
}

Copy | Download

TY  - JOUR
T1  - Low-dose Methotrexate Toxicity in Ectopic Pregnancy: 
A Case Report and Literature Review
AU  - Jia-Chen Cheng
AU  - Wen-Yang Xie
AU  - Xue Wu
AU  - Pu Li
Y1  - 2026/01/30
PY  - 2026
N1  - https://doi.org/10.11648/j.jgo.20261401.13
DO  - 10.11648/j.jgo.20261401.13
T2  - Journal of Gynecology and Obstetrics
JF  - Journal of Gynecology and Obstetrics
JO  - Journal of Gynecology and Obstetrics
SP  - 30
EP  - 36
PB  - Science Publishing Group
SN  - 2376-7820
UR  - https://doi.org/10.11648/j.jgo.20261401.13
AB  - 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.
VL  - 14
IS  - 1
ER  -

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