Careful patient selection is the key to successful and safe management of ectopic
pregnancy with methotrexate treatment (see below). It should be offered as a first-line
treatment to women with unruptured ectopic pregnancy with serum HCG < 1500 IU/L
and offered as an option for treatment of unruptured ectopic pregnancy with serum
HCG < 5000 IU/L.
2) Objective of Guideline
The aim is to ensure appropriate selection of patients for methotrexate treatment and to
give guidance on how to effect the treatment and organise appropriate follow up.
3) Rationale for the recommendations
Management of ectopic pregnancy can be conservative, medical or surgical.
Women who meet the criteria below can be successfully treated medically using
the single- dose methotrexate 50mg per m2 (IM).
Methotrexate is safe and effective in the medical treatment of unruptured ectopic
pregnancy. Overall, success rates of single-dose methotrexate range from 65-
95%. The success rate of methotrexate was found to be 90% in the largest study
to date.
There are a number of predictors of success :
1) Initial serum HCG (Human chorionic gonatrophin) level – success rates are
higher with lower HCG levels. Success rates of 81-98% have been reported if
serum HCG levels are less than 1000 iu/l compared to only 38% if HCG levels
are greater than 5000 iu/l.
2) Ultrasound appearance of the ectopic pregnancy – success rates are higher
when no gestational sac is visualised. Presence of yolk sac, fetal pole and / or
fetal cardiac activity are significant predictors of failure.
3) Pretreatment changes in serum HCG levels – the smaller the increase in
HCG level prior to administration of methotrexate, the higher the chance of
successful medical treatment. An increase of up to 11 – 20% over 48 hours prior
to the administration of methotrexate has been associated with higher rates of
success.
4) Decrease in HCG level from day 1 to day 4 after methotrexate – success
rates of 88-100% have been reported if serum HCG level decreases from day 1
to day 4 post administration of methotrexate compared to only 42-62% if the
serum HCG level increases.
If the treatment is successful, the tube is conserved with good chance of patency
(80%). Subsequent fertility appears to be as good as conservative therapy
(>70%) and the risk of recurrent ectopic is the same (10%). In about 10%,
surgery will be required as the ectopic ruptures during treatment or hCG levels
do not drop as expected.
The disadvantages of methotrexate therapy are the risk of adverse effects and
the need for compliance in follow-up to ensure resolution of pregnancy. The most common side effects of methotrexate include excessive flatulence and bloating
(due to intestinal gas formation), stomatitis and a transient mild elevation in liver
enzymes.
Serious adverse effects include bone marrow suppression, pulmonary fibrosis,
nonspecific pneumonitis, liver cirrhosis, renal failure and gastric ulceration. In this
regimen toxicity is unlikely and most of these effects resolve spontaneously
within 4 weeks of treatment.
4) Inclusion criteria
Clinical characteristics
1. Certainty that there is no intrauterine pregnancy
2. Woman clinically stable with no evidence of intraperitoneal bleeding
3. Minimal pain
4. βhCG < 1500IU but can be considered with values < 5000IU
5. No fetal heart activity on scan
6. Ectopic mass < 35 mm
Patient characteristics
1. Would prefer medical option
2. Willing to attend EPAU follow-up
3. Willing to avoid sexual intercourse during treatment
4. Prepared NOT to get pregnant for 3 months following treatment
5) Contraindications to medical management with methotrexate
1. Thrombocytopenia (platelet count < 100,000) or blood dyscrasia (WBC < 2000)
2. Hepatic or renal dysfunction
3. Immunocompromise or concurrent corticosteroid therapy
4. Sensitivity to methotrexate
5. Breastfeeding
6. Peptic ulcer disease
7. Active pulmonary disease
8. Haemodynamic instability
Pre-treatment bloods
FBC, Group & save serum
serum HCG, U&Es, LFTs
If anaemic reconsider whether treatment is appropriate (i.e. should surgical
management be reconsidered)
White cell count, platelets, U&Es and LFTs should be normal before treatment.
5. Prescribe Methotrexate 50 (fifty) milligrams per m2. Pharmacy will calculate the
surface area if the woman’s height and weight are given on the prescription chart
and will calculate the exact dose based on surface area. Pharmacy will issue a
syringe with exact dose during week days. However over the weekend (Saturday
and Sunday) pharmacy will provide a pre-filled syringe (90 mg in 3.6 mL i.e. 25
mg/mL) and the doctor on call will have to give the closest possible dose. If the
patient is stable treatment may be deferred until the next working day.
6. Methotrexate is given intramuscularly in buttock or lateral thigh. The empty syringe
or needle should be placed in a separate Sharp Safe, labelled “Cytotoxic waste for
special incineration”.
7. Do not offer anti-D prophylaxis to rhesus negative women who receive solely medical
management.
8. Give instructions about the symptoms of ectopic rupture. Note: transient abdominal
discomfort occurs in more than 50% of women 3-7 days after the initiation of
treatment due to separation pain. It is mild and normally lasts 4-12 hours and is never
associated with an acute abdomen or haemodynamic instability. Significant free fluid
on ultrasound scan would suggest ectopic pregnancy rupture and requires
emergency surgery.
9. Sexual intercourse should be avoided. Aspirin or other NSAIDs should not be taken.
A discharge letter should be sent to the GP.
10. Follow-up in EPAU
Serum HCG on Day 4 following methotrexate
Serum HCG, FBC and LFTs on Day 7
Ultrasound scan on day 7 only if suboptimal fall in HCG (<15%) between
day 4-7 or the patient is symptomatic with increasing pain
Note: A rise in HCG is expected on day 4 of the treatment but thereafter the HCG
should fall by >15% between day 4-7. If this drop does not occur, a repeat transvaginal
ultrasound scan should be considered to exclude ectopic fetal cardiac activity and/or
haemoperitoneum. Once this has taken place to exclude these indications for surgical
management, a second dose of methotrexate may be considered (needed in 3-27% of
patients). Consultant involvement in decision making is needed.
If the HCG fall between day 4-7 is >15%, then repeat HCG weekly until
<15 IU.
Note resolution is slow - median 5 weeks with maximum up to 8 weeks.
11. Review if symptomatic. Check FBC and ultrasound to detect free fluid.
12. Women must avoid pregnancy after methotrexate for 3 months. Effective
contraception should be recommended (e.g. combined oral contraceptive pill). If
women wish to discuss additional methods, refer to the iCASH Clinic.
13. Women should be made aware of the increased risk of ectopic pregnancy in future
pregnancies (10%) and that an early scan at 6-7 weeks gestation is recommended
to ensure that the pregnancy is intrauterine.
7) Clinical Audit Standards derived from guideline
Success rate of methotrexate treatment (gold standard 90%)
8) References / source documents
1. Lipscombe M. et al. Methotrexate therapy of tubal pregnancy. N Engl J Med 1999;
341: 1974-8.
2. Murray H, Baakdah H, Bardell T, Tulandi T. Diagnosis and treatment of ectopic
pregnancy. Canadian Medical Association Journal 2005; 173(8):905-912
3. Farquhar CM. Review on ectopic pregnancy. Lancet 2006; 367(9504):27 PMID
6399146-8
4. RCOG Guideline No.21 ‘Diagnosis and management of ectopic pregnancy’
November 2016
5. Kirk E, Condous G, Bourne T. The non-surgical management of ectopic pregnancy.
Ultrasound Obstet Gynecol. 2006 271:91-100.
6. NICE clinical guideline 154. Diagnosis and initial management in early pregnancy
of ectopic pregnancy and miscarriage.