Alternative Follow-Up Regimen for Methotrexate Treatment

After methotrexate administration to treat and ectopic pregnancy, patients follow-up for a laboratory evaluation to measure human chorionic gonadotropin (hCG) response. This follow up occurs on day 4 and 7, with day 1 being the day of methotrexate administration. With no validated alternative, patients may have difficulty adhering to this follow-up schedule. The objective of this retrospective cohort study was to compare outcomes of monitoring patients on days 4 and 7 to days 5 and 8 following methotrexate administration for confirmed or suspected ectopic pregnancies.

We performed a retrospective cohort analysis within the Military Health System, identifying individuals treated with methotrexate for either confirmed or suspected ectopic pregnancy between 2016 and 2025. Cases were identified using ICD-10 diagnostic codes, followed by manual chart review to collect: demographics, obstetric history, initial hCG level, follow-up schedule, subsequent hCG levels after treatment, dose(s) of methotrexate administered, whether surgical intervention was required. Regardless of cohort, treatment response was characterized by a ≥15% decline in serum hCG between monitoring days without surgical intervention. Patients monitored on post-treatment days 5 and 8 following methotrexate were compared with those followed on days 4 and 7. Exclusion criteria included an initial hCG level greater than 5,000 mIU/mL, planned two-dose methotrexate protocols, or lost to follow-up. Treatment success was defined as a final hCG level less than 25 mIU/mL. Statistical comparisons were conducted using Fisher's exact test and Mann-Whitney U test, as appropriate. This study was deemed exempt by our institution's IRB (WRNMMC-EDO-2025-1355).

We identified 136 patients, 100 patients monitored on days 4 and 7, and 36 patients monitored on days 5 and 8. There were no statistical differences in patient age at time of methotrexate administration, ethnicity/race, gravidity and parity, and history of ectopic pregnancy. Baseline methotrexate dose (4/7: 91.5 mg/m2, 5/8: 92.2 mg/m2) and initial hCG (4/7: 1350.2 mIU/mL, 5/8: 1341.1 mIU/mL) were similar between groups. The majority of patients in both cohorts had a successful response to methotrexate (4/7: 60.0%, 5/8: 63.9%). Of these responders, methotrexate without additional intervention was successful in the majority of cases (4/7: 96.7%, 5/8: 91.3%). Frequencies of treatment success were 79/83 (95.2%) in patients who did versus 45/54 (83.3%) in patients who did not have a treatment response (OR 3.95, 95% CI [1.21, 15.3]).

Following up on days 5 and 8 or days 4 and 7 post-methotrexate treatment led to similar outcomes in ectopic pregnancies. These data provide reassuring evidence that the appropriately counseled patient can follow-up on day 5 and 8, rather than 4 and 7, after methotrexate administration and still be safely managed.