Methotrexate (MTX) Protocol in Ectopic Pregnancy (EP):
Methotrexate Pretreatment Investigations:
– Viable IUP must be excluded.
– Serum hCG: as part of the diagnostic evaluation & to establish a baseline to monitor the effect of therapy.
– TVUS: as part of the diagnostic evaluation.
– Bl. group & Rh: to determine the need for anti-D Ig.
– CBC, kidney & liver function tests: to assess for CI to MTX.
Methotrexate Pretreatment Instructions:
– Discontinue folic acid supplements.
– Avoid NSAID & give paracetamol if an analgesic is needed.
– Avoid sexual intercourse & strenuous exercise.
Methotrexate Single Dose Protocol (the preferred for tubal EP):
– Administration of a single IM dose of MTX.
– 15-20% of women will require a 2nd dose & patients should be aware of this before starting the protocol.
– The overall rate of resolution of EP is approximately 90% for both single- & multipledose protocols.
– Advantage: less side effects, requires less monitoring & doesn’t require folinic acid rescue (leucovorin).
– Method:
• Day 1 is the day that MTX is administered (1 mg/kg & maximum 1.5 mg/kg IM).
• On Days 4 & 7, serum hCG is measured.
• On Days 7, if <15% hCG decline from day 4 to 7, give 2nd dose of MTX.
• If ≥15% hCG decline from day 4 to 7, check hCG weekly until undetectable.
• On Days 14, if <15% hCG decline from day 7 to 14, give 3rd dose of MTX.
• If ≥15% hCG decline from day 7 to 14, check hCG weekly until undetectable.
• We give a maximum of 3 doses in the single protocol.
• If 3 doses have been given & there is a <15% hCG decline from day 14 to 21, we
perform a laparoscopic salpingostomy or salpingectomy.
Methotrexate Important Points Regarding Single-dose protocol:
– It is common to observe an increase in hCG levels in the first days following therapy (until Day 4); this is due to continued hCG production by syncytiotrophoblast despite cessation of production by cytotrophoblast.
– If an additional dose of MTX is indicated, we don’t repeat pretreatment investigations.
– Folinic acid rescue (leucovorin) is not required for women treated with the single-dose protocol, even if multiple doses are ultimately given.
– If the hCG doesn’t decline to zero or rising, TVUS should be performed & a new pregnancy should be excluded.
– There is no clinical benefit from routine serial TVUS examinations. However, TVUS evaluation for peritoneal fluid is indicated for women with severe abdominal pain.
– After treatment, the EP is often increase in size & may persist for weeks on serial TVUS examinations. This probably represents hematoma rather than persistent trophoblastic tissue & is not predictive of treatment failure.
– Falling hCG levels don’t exclude the possibility of tubal rupture.
– If tubal rupture is suspected, immediate surgery is required.
Methotrexate Multiple Dose Protocol:
– 4 MTX doses alternating with oral leucovorin (the antidote) are used.
– It is used for interstitial pregnancies & cervical pregnancy (relatively more trophoblastic tissue than tubal pregnancy).
– Advantage: lower failure rate.
– Disadvantage: more adverse effects (so, leucovorin is used).
– Method:
• Administers MTX (1 mg/kg/day) IM or IV on Days 1, 3, 5 & 7 & oral leucovorin (0.1 mg/kg) on Days 2, 4, 6 & 8.
• HCG is checked on Days 1, 3, 5 & 7.
• If <15% hCG decline from day 1 to 3 (suspected), give MTX 2nd dose followed by leucovorin the next day.
• If ≥15% decline from day 1 to 3, stop treatment & begin surveillance (weekly HCG) as in the single protocol.
• These last 2 steps are applied at every point along the course.
• On Days 14, if <15% hCG decline from day 7 to 14, give 5th dose of MTX followed by leucovorin the next day.
• If ≥15% hCG decline from day 7 to 14, check hCG weekly until undetectable.
• If 5 doses have been given & there is a <15% hCG decline from day 14 to 21, proceed with laparoscopic surgery.
Methotrexate Precautions during Therapy:
– Avoid vaginal intercourse & new conception until hCG is undetectable.
– Avoid foods & vitamins containing folic acid.
– Avoid NSAID, as the interaction with MTX may cause bone marrow suppression, aplastic anemia & GIT toxicity.
– Avoid pelvic exams during surveillance of MTX therapy due to theoretical risk of tubal rupture.
– Avoid sun exposure to limit risk of MTX dermatitis.
Methotrexate Pain After Treatment:
– Mild to moderate abdominal pain of short duration (1-2 days) 6-7 days after receiving the medication is common.
– The pain may be due to tubal abortion or tubal distention from hematoma formation & can be controlled with paracetamol.
– If severe pain in hemodynamically stable woman, no need for surgical intervention.
– Findings suggestive of hemoperitoneum raise the suspicion of tubal rupture.
– Women with severe pain should be evaluated with TVUS & closely observed for hemodynamic changes which may accompany a tubal rupture.
– 3 parameters predicted hemoperitoneum ≥300 ml in women with EP:
1. Moderate to severe pelvic pain.
2. Fluid above the uterine fundus or around the ovary.
3. Serum Hb<10 g/dl. When ≥2 criteria are present, the probability for hemoperitoneum ≥300 ml is 92%.
Methotrexate Interval to Conception:
– We advise women not to conceive for 3 months.
– On the other hand, there is no evidence of teratogenic risk to those who conceive sooner.
– EP pregnancies treated with MTX have a timely return of menses & superior rates of conception compared with those treated with salpingostomy.
– These women should take folic acid daily, according to routine preconceptional recommendations.