How should a hemodynamically stable woman with an unruptured ectopic pregnancy (serum β‑hCG ≤5,000 IU/L, gestational sac ≤3.5 cm, no cardiac activity, no contraindications) be medically managed with methotrexate?

Medical Management of Ectopic Pregnancy with Methotrexate

Administer methotrexate 50 mg/m² as a single intramuscular injection, with follow-up β-hCG monitoring on days 4 and 7, and provide a second dose if β-hCG fails to decline by ≥15% between days 4 and 7. 1

Pre-Treatment Requirements

Before administering methotrexate, obtain the following laboratory tests 1:

• Complete blood count with differential and platelet counts
• Liver function tests (AST, ALT)
• Renal function tests (creatinine, BUN)

Confirm the patient meets all eligibility criteria 1:

• Hemodynamically stable with normal vital signs
• Unruptured ectopic pregnancy confirmed on ultrasound
• Ectopic mass ≤3.5 cm in greatest dimension
• β-hCG ≤5,000 mIU/mL (preferably)
• No embryonic cardiac activity on ultrasound
• Able and willing to comply with close follow-up

Critical Contraindications to Screen For

Absolute contraindications include 1:

• Active liver, kidney, lung, or hematopoietic system disease
• Immunodeficiency
• Alcoholism
• Peptic ulcer disease
• Breastfeeding (must discontinue immediately and wait ≥3 months after last dose to resume) 1

Relative contraindications include 1:

• Embryonic cardiac motion on ultrasound
• Ectopic gestational sac >3.5 cm

Treatment Protocol

Initial Dose

Administer methotrexate 50 mg/m² (or 1 mg/kg) as a single intramuscular injection 1, 2. This is the standard single-dose protocol recommended by the American College of Emergency Physicians 1.

Medication Interactions to Avoid

Instruct the patient to avoid the following medications 1:

• Folic acid supplements (counteract methotrexate's mechanism of action)
• NSAIDs (ibuprofen, naproxen)
• Aspirin These interactions can be potentially lethal and must be strictly avoided 1.

Rh Status Management

For Rh-negative women, administer anti-D immunoglobulin (RhoGAM) to prevent alloimmunization 1.

Follow-Up Monitoring Protocol

β-hCG Monitoring Schedule

Measure serum β-hCG levels on 1:

• Day 1 (day of injection)
• Day 4 (to establish trend, though this does not predict success) 3
• Day 7 (critical decision point)

Expect β-hCG levels to initially plateau or even rise slightly in the first 1-4 days before declining 1. This is normal and does not indicate treatment failure.

Criteria for Second Dose

Administer a second dose of methotrexate 50 mg/m² if β-hCG fails to decrease by ≥15% between days 4 and 7 1. The second dose successfully resolves most treatment failures, with overall success rates of 88-94% when multiple doses are used 1, 4.

Continue monitoring β-hCG every 1-2 weeks until levels normalize to <5 mIU/mL 1.

When to Escalate to Surgery

Proceed immediately to surgical management if 1, 5:

• Patient develops hemodynamic instability (hypotension, tachycardia)
• Severe or worsening abdominal pain suggesting rupture
• Heavy vaginal bleeding
• Shoulder pain (indicates diaphragmatic irritation from hemoperitoneum)
• β-hCG plateaus over three consecutive measurements after second dose
• β-hCG increases over two consecutive measurements after second dose

Expected Outcomes and Success Rates

Success rates for single-dose methotrexate range from 71-96%, with approximately 12% of patients requiring a second dose 1. When β-hCG is ≤5,000 mIU/mL, success rates are at the higher end of this range 1, 4.

Treatment failure occurs in 3-36% of cases overall, with rupture rates of 0.5-19% 1. Higher failure risk is associated with 1, 4:

• β-hCG >5,000 mIU/mL (significantly higher failure rates)
• Larger ectopic masses approaching 3.5 cm
• Presence of embryonic cardiac activity

The median time to rupture after methotrexate administration is 14 days, with a maximum of 32 days, so vigilance must be maintained throughout the monitoring period 5.

Patient Education and Warning Signs

Critical Warning Signs Requiring Immediate Emergency Care

Instruct the patient to seek immediate medical attention for 1, 5:

• Severe or sudden worsening abdominal pain (most important warning sign of rupture)
• Shoulder pain (diaphragmatic irritation from blood)
• Heavy vaginal bleeding
• Dizziness, lightheadedness, or fainting
• Signs of shock (rapid heartbeat, cold/clammy skin, confusion)

Expected Side Effects

Common side effects that do NOT require emergency care include 1:

• Mild nausea and vomiting (30% of patients)
• Mild abdominal cramping or discomfort
• Gastritis (7%)
• Stomatitis (mouth sores, 7%)

Important caveat: Gastrointestinal side effects from methotrexate can mimic acute ectopic rupture 1. If the patient develops significant abdominal pain, rule out rupture with clinical assessment and ultrasound before attributing symptoms to drug toxicity.

Common Pitfalls and How to Avoid Them

Do not prescribe methotrexate remotely or without verified ultrasound findings and laboratory results 1. Patients whose hemodynamic stability, ultrasound findings, and laboratory results cannot be verified should be considered for surgical management instead.

Do not use methotrexate when β-hCG is significantly >5,000 mIU/mL 1. At β-hCG levels of 14,000 mIU/mL, for example, treatment failure rates approach 27-29% with rupture rates of 17-19% 1. This exposes the patient to weeks of monitoring with high rupture risk and likely surgical intervention anyway.

Ensure close follow-up is feasible 1. Patients unable or unwilling to comply with frequent monitoring and follow-up appointments are not candidates for medical management.

For patients who conceived through IVF, ensure no intrauterine pregnancy coexists before proceeding 1. The risk of heterotopic pregnancy is higher with assisted reproductive technologies.