In a 35-year-old woman with a left tubal ectopic pregnancy treated with methotrexate who is asymptomatic but has plateauing serum beta‑human chorionic gonadotropin (β‑hCG) levels on day 4 and day 7, what is the most appropriate next management step?

Second Dose of Methotrexate

The most appropriate next step is to administer a second dose of methotrexate (Option C). 1

Rationale for Second Dose Administration

Plateauing β-hCG levels between day 4 and day 7 after initial methotrexate administration is a clear indication for a second dose, provided the patient remains hemodynamically stable with no signs of rupture. 1 The American College of Emergency Physicians specifically recommends a second dose when β-hCG levels fail to decrease appropriately or plateau after initial treatment. 1

Expected β-hCG Pattern After Methotrexate

• After methotrexate administration, β-hCG levels may initially plateau or even rise slightly in the first 1-4 days before declining—this is a normal physiologic response. 1
• The standard protocol requires monitoring β-hCG on days 4 and 7 to assess treatment response. 1
• A plateau (lack of decline) between these timepoints indicates treatment failure with the initial dose. 2, 3

Evidence Supporting Second Dose Efficacy

• Treatment failure with single-dose methotrexate occurs in 3-36% of cases, and a second dose successfully resolves most treatment failures. 1
• Overall success rates for single-dose methotrexate range from 71-96%, with approximately 12% of patients requiring a second dose. 1
• Studies demonstrate that 94% of ectopic pregnancies can be successfully managed with systemic methotrexate, including cases requiring multiple doses. 1
• Second-dose methotrexate is successful in approximately 79% of patients who require it. 4

Why Other Options Are Incorrect

Option A (Laparoscopic Salpingectomy) - Incorrect

• Surgical intervention is indicated only if the patient develops hemodynamic instability or signs of rupture. 1
• This patient is asymptomatic, making surgery premature at this stage. 1
• The American College of Emergency Physicians recommends close surveillance for rupture symptoms (severe abdominal pain, hemodynamic instability, heavy vaginal bleeding, or shoulder pain) before proceeding to surgery. 1

Option B (Repeat β-hCG in One Week) - Incorrect

• Waiting one week without intervention when β-hCG has already plateaued delays necessary treatment. 1
• The standard protocol calls for intervention when plateau is identified between days 4 and 7, not further observation. 3
• Prolonged monitoring without treatment increases rupture risk (0.5-19% across studies). 5

Option D (Repeat β-hCG in 48 Hours) - Incorrect

• The plateau has already been documented between days 4 and 7, making further short-interval monitoring without treatment inappropriate. 3
• The decision point for second-dose administration has been reached based on the established protocol. 1

Critical Safety Monitoring After Second Dose

Patients must be counseled to return immediately for:

• Severe abdominal pain (may indicate rupture). 1
• Signs of hemodynamic instability (tachycardia, hypotension, dizziness). 1
• Heavy vaginal bleeding. 1
• Shoulder pain (indicating diaphragmatic irritation from hemoperitoneum). 1

Common Pitfall to Avoid

Do not attribute gastrointestinal symptoms (nausea, abdominal pain) to methotrexate toxicity without first ruling out ectopic rupture. 1 These symptoms can mimic acute ectopic rupture, and rupture should be excluded before attributing symptoms to drug side effects. 1

Follow-Up Protocol After Second Dose

• Continue monitoring β-hCG levels at least every 1-2 weeks until normalization. 6
• If β-hCG plateaus over 3 consecutive cycles or rises over 2 consecutive cycles after the second dose, surgical intervention becomes necessary. 6
• Methotrexate treatment failure requiring delayed surgery occurs in 15-23% of cases overall. 1