Methotrexate Ectopic Protocol

Aka: Methotrexate Ectopic Protocol

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II. Indications: Ectopic Pregnancy Criteria

  1. Hemodynamically stable
  2. Quantitative bhCG < 5,000 mIU/ml
    1. Some recommend limiting Methotrexate protocol to bHCG <2000 mIU/ml (see efficacy below)
  3. Ectopic Pregnancy fully visualized on Ultrasound
    1. Embryo size under 3 cm
    2. Tubal serosa intact (no rupture)
    3. No fetal heart activity
  4. Normal lab testing (see screening below)
  5. No active bleeding

III. Advantages

  1. Allows for possible future fertility on affected side

IV. Contraindications

  1. Active lung disease
  2. Lactation
  3. Immunodeficiency
  4. Poor compliance
  5. History Peptic Ulcer Disease
  6. Fetal cardiac activity noted on Ultrasound
  7. Ectopic mass >3.5 to 4 cm
  8. Gestational Sac >3.5 cm
  9. Blood dyscrasias
    1. White Blood Cell Count <3000 (Leukopenia)
    2. Platelet Count <100,000 (Thrombocytopenia)
    3. Severe Anemia
  10. Liver disease or elevated Aspartate Aminotransferase (AST)
    1. Methotrexate has hepatotoxicity potential
  11. Renal Disease or decreased Creatinine Clearance <50 ml/min/1.73 m3
    1. Methotrexate is renally excreted
  12. bHCG >5000 mIU/ml
    1. Some recommend a relative contraindication at bHCG >2000 mIU/ml (see efficacy below)

V. Efficacy

  1. bHCG <1000 mIU/ml
    1. Success Rate: 88-98%
  2. bHCG <1000 to 2000 mIU/ml
    1. Success Rate: 71-94%
  3. bHCG <2000 to 3000 mIU/ml
    1. Success Rate: 59-96%
  4. bHCG <3000 to 4000 mIU/ml
    1. Success Rate: 50-96%
  5. bHCG >4000 mIU/ml
    1. Success Rate: 42-85%
  6. References
    1. Menon (2007) Fertil Steril 87(3): 481-4 [PubMed]
    2. Sagiv (2012) Int J Gynaecol Obstet 116(2): 101-4 [PubMed]

VI. Labs: Baseline

  1. Serum Creatinine
  2. Liver Function Tests
  3. Complete Blood Count with differential
  4. Quantitative bhCG
  5. Serum Progesterone may also be followed
    1. Anticipate drop to 1.5 mg/ml by 2-3 weeks

VII. Approach: General

  1. Obtain baseline labs and review contraindications
  2. Choose a single dose or two dose protocol
    1. bHCG <3600 IU/L: Single Dose Protocol
    2. bHCG >3600 IU/L: Two Dose Protocol
  3. Use Contraception and avoid pregnancy until at least 1-3 ovulatory cycles from bHCG undectable
  4. Monitor patients closely on Methotrexate protocol
    1. Ectopic Pregnancy rupture risk continues until bHCG is undetectable
  5. Anticipatory guidance
    1. Review adverse effects as below
    2. Abdominal Pain may occur 2-3 days after Methotrexate
      1. See Below
    3. Avoid agents that suppress Methotrexate effect
      1. NSAIDs
      2. Folic Acid
    4. Avoid activities that increase Ectopic Pregnancy rupture risk
      1. Avoid vaginal intercourse
      2. Avoid strenuous Exercise

VIII. Protocol: Single Dose

  1. Preferred protocol for lower HCG levels (fewer adverse effects than two dose ot multiple dose regimens)
    1. Recommended for bHCG <3600 IU/L
  2. Adjuncts (some protocols)
    1. Consider Leucovorin rescue
  3. Outcomes
    1. Success rate: 88.1% if starting bHCG <1000 mIU/ml (>1 dose needed in 14% of cases)
    2. Adverse effects: 31.3%
      1. See Methotrexate
  4. Day 1
    1. Obtain Baseline labs above (CBC, Chem18)
    2. Measure bHCG
    3. Methotrexate 50 mg/m2 BSA IM (some protocols have used IV or PO)
  5. Day 4
    1. Measure bHCG
  6. Day 7
    1. Measure bHCG
      1. Anticipate 25% bHCG decrease between days 1 and 7
      2. Anticipate 15% bHCG decrease between days 4 and 7
    2. If bHCG decreases >15% between days 4 and 7
      1. Recheck bHCG each week until undetectable
      2. Anticipate bHCG drop to 5 mIU/ml by 3-4 weeks
      3. Contraception until bHCG returns to 5 mIU/ml or less
    3. If bHCG decreases <=15% between days 4 and 7
      1. Surgical Management OR
      2. Repeat Methotrexate 50 mg/m2 BSA IM and bHCG once
        1. Surgical management If bHCG decreases <15% between bHCG draws

IX. Protocol: Two-Dose

  1. Preferred protocol for higher HCG levels (higher efficacy than single dose protocol)
    1. Recommended for bHCG >3600 to 5000 IU/L
  2. Day 1
    1. Obtain Baseline labs above (CBC, Chem18)
    2. Measure bHCG
    3. Methotrexate 50 mg/m2 BSA IM (some protocols have used IV or PO)
  3. Day 4
    1. Measure bHCG
    2. Methotrexate 50 mg/m2 BSA IM (some protocols have used IV or PO)
  4. Day 7
    1. Measure bHCG
    2. If bHCG decreases >15% between days 4 and 7
      1. Recheck bHCG each week until undetectable
      2. Contraception until bHCG returns to 5 mIU/ml or less
    3. If bHCG decreases <=15% between days 4 and 7
      1. Surgical Management OR
      2. Repeat Methotrexate 50 mg/m2 BSA IM and bHCG on Day 7, 11 and 14
        1. Surgical management If bHCG decreases <15% between bHCG draws

X. Protocol: Multiple Dose (older protocol)

  1. Contraception until bHCG returns to 5 mIU/ml or less
  2. bHCG monitoring as below
  3. Alternate agents up to 4 doses of each drug
    1. Methotrexate 1 mg/kg PO or IV on days 1, 3, 5, and 7
    2. Leucovorin 0.1 mg/kg on days 2, 4, 6, and 8
  4. Outcomes
    1. Success rate: 92.7%
    2. Adverse effects: 41.2%

XI. Adverse Effects

  1. Mild Abdominal Pain
    1. Typically onset days 2-3 following Methotrexate start
    2. Resolves within 24-48 hours
    3. Pain appears to be associated with separation of implanted pregnancy
    4. Distinguish from Abdominal Pain of tubal rupture
      1. May be more severe
      2. May be associated with hemodynamic instability
      3. Obtain immediate HCG and Transvaginal Ultrasound if any signs not consistent with typical Methotrexate protocol pain
  2. Vaginal Bleeding
  3. Gastrointestinal distress
    1. Nausea or Vomiting
    2. Diarrhea
    3. Flatulence or bloating (common)
  4. Lab and diagnostic changes
    1. bHCG transiently increased on starting Methotrexate
    2. LFTs may transiently increase (typically <2 fold increase) on starting Methotrexate
    3. Size of ectopic may asymptomatically increase in up to 56% of women (associated with Hematoma formation)
  5. Methotrexate photosensitivity and dermatitis
    1. Use Sunscreen

XII. Prognosis

  1. Recurrent Ectopic Pregnancy risk: 10-20%
  2. Chance of subsequent intrauterine pregnancy: 40-60%

XIII. References

  1. Kuppusamy (2013) Crit Dec Emerg Med 27(7): 2-7
  2. (2018) Obstet Gynecol 131(3):e91-103 [PubMed]
  3. (2008) Obstet Gynecol 111(6): 1479-85 [PubMed]
  4. Barash (2014) Am Fam Physician 90(1): 34-40 [PubMed]
  5. Barnhart (2003) Obstet Gynecol 101:778-84 [PubMed]
  6. Hendriks (2020) Am Fam Physician 101(10): 599-606 [PubMed]
  7. Lipscomb (1999) N Engl J Med 341:1974-8 [PubMed]

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