Medical Management of Ectopic Pregnancy

Abstract

Methotrexate is the standard medical management for ectopic pregnancy. Pharmacologically, it is a folic acid antagonist which inhibits DNA synthesis. 90% of appropriately selected un-ruptured none live ectopic pregnancy respond to methotrexate treatment with no further management is required. In the UK, NICE guidance has identified the selection criteria to achieve the best and safest outcome in ectopic pregnancy treatment with methotrexate. Methotrexate also has a role in management of pregnancy of unknown location. Single administration of 50 mg/m2 body surface area is the most widely acceptable regimen for methotrexate in treatment of ectopic pregnancy. Post treatment b-HCG checks at day 0, 4 and 7 are also a widely accepted follow up regimen to ensure satisfactory decline in b-HCG levels. Methotrexate has a role also in managing none tubal ectopic pregnancies where surgical risks are high. Post treatment transient pain is common and represent a clinical challenge as it can also be failed treatment with ruptured ectopic pregnancy.

1. Introduction

Single dose of 50 mg/m2 body surface area is the most widely acceptable regimen for methotrexate in treatment of ectopic pregnancy. In carefully selected cases it has comparable success rate to surgical management and avoiding the relevant risks associated with surgical approach [1, 2]. 90% of appropriately selected un-ruptured none live ectopic pregnancy respond to methotrexate treatment with no further management is required [3]. Post treatment b-HCG checks at day 1, day 4 and 7 are also a widely accepted follow up regimen to ensure satisfactory decline in b-HCG levels [4].

2. Pharmacology of methotrexate

Methotrexate is a folate antagonist that eneters the cells by active transport process. Once in the cell it becomes polyglutamated and binds dihydrofolate reductase enzyme which subsequently deprive the cell of the folic acid coenzymes. Folic acid co-enzymes are essential for nucleic acid and protein synthesis. Methotrexate suppression of dihydrofolate reductase leads to significant reduction in DNA, RNA and intracellular protein synthesis and ultimately cell death [5]. The most common side effects are nausea, vomiting and diarrhoea. Less commonly it can cause stomatitis, erythema, rash, alopecia and urticaria. Uncommon but serious side effects are also the impacts of its administration on renal and hepatic function. Pretreatment liver and kidney function tests are important as its administration should be carefully weighted with side effects in patients with pre-treatment impaired hepatic and/or kidney functions [5].

3. Selection criteria

Appropriate patient selection is essential for considering the methotrexate in patient with ectopic pregnancy. Appropriate candidate should has; [6, 7, 8].

Haemodynamic stability.

Serum b-hCG between under 5000 iu.

No fetal cardiac activity seen on ultrasound scan.

No intrauterine pregnancy.

No significant pain.

Un-ruptured ectopic pregnancy with a mass smaller than 35 mm.

Minimal (under 100 ml) or no free fluid in pouch of Douglas on scan.

No liver, renal impairment.

No bone marrow impairment evidenced by leukopenia, thrombocytopenia or anaemia.

4. Administration

Women who choose this form of treatment should be given written information leaflet and advice about potential of abdominal pain after the treatment and informing to seek medical attention in such situations [9, 10].

Women also should be avoid consuming alcohol, folate containing vitamins and excessive exposure to sun (risk of photosensitive skin reaction) in the post treatment period [11].

Day 1 - FBC check as well as b-hCG, U&Es and Liver function tests. Also women should have blood group and Rh status checked.

Day 4 - symptoms check and b-hCG.

Day 7 - symptoms check and b-hCG, FBC, U&Es and Liver function tests.

Fall of b-hCG levels between day 4 and day 7 should be more than 15% and weekly after day 7 till the b-hCG levels are less than 15 iu.

If less than 15% decrease is reported or levels remains static a second dose of methotrexate should be considered provided a repeat Ultrasound is done exclude fatal cardiac activity and/or appearance of haemoperitonium.

5. Contraindication to methotrexate

Patient who is unstable haemodynamically [12, 13].

Presence of an intrauterine pregnancy.

Breastfeeding.

Previous sensitivity to methotrexate.

Chronic liver disease.

Chronic kidney disease.

Immunodeficiency.

Patient with known bone marrow suppression.

6. Success of methotrexate

With appropriate selection of candidates, methotrexate success can be as high as 91%. There are notable variation across various units in relation to success rates (65–96%) which is especially related the cut off point of b-hCG level for methotrexate consideration.

Approximately 13% requires a second dose of methotrexate with a range of 3–27%.

The most important factors identified for determining the success of the methotrexate treatment includes;

Pre-treatment b-hCG levels; success rate can be as high as 98% with initial levels are under 1000 iu and as low as 38% if the initial levels are over 5000 iu [12].

Pre- treatment ultrasonic findings; presence of fatal pole with cardiac activity is associated with higher failure rate and it is considered a contraindication for methotrexate administration [12, 13, 14].

Post - treatment drop in b-hCG; success rates approaches 90% with decrease in b-hCG levels between day 1 and day 4 and between 4 and day 7. This compared to approximate success of 40% if b-hCG levels increase and 60% if the the levels remain static [15, 16].

7. Comparison to expectant management

The use of single dose methotrexate systematically is associated with definite higher success in treatment of ectopic pregnancies compared to expectant management. The expectant management is considered for patients who are asymptomatic and b-hCG under 1500 iu and no free fluid in pouch of Douglas as well as sac under 3 cm in diameter with no metal cardiac activity. Also, the expectant management are considered in asymptomatic patients with pregnancy of unknown location (PUL). Randomised controlled trial concluded a success rate 76% in methotrexate group compared to 59% to expectant management group [17].

8. Comparison to surgical management

Compared to the surgical option in those who meet the selection criteria, Methotrexate associated with lower treatment cost, no hospital admission and no surgical risks. Furthermore, evidence reported no difference in future pregnancy outcomes [18].

9. Post treatment pain

Treatment with methotrexate can be associated with post treatment pain which usually occurs between day 3 and day after its administration. It is mainly due tubal abortion and can stay up to 24 hours. Post treatment pain is a clinical challenge as it cannot distinguished from tubal rupture associated with failed treatment. The consideration for hemodynamic state, full clinical review as well as ultrasound feature defines the next step. Post treatment pain is managed expectantly while tubal rupture requires surgical intervention [19, 20].

10. Post methotrexate anti-D

There are limited evidence to recommend the use of anti-D in those enraptured ectopic pregnancies which meet the selection criteria as likelihood of maternal sensitisation is low. The evidence are strong regarding the use of anti-D with surgical management especially the ruptured cases where the chances of maternal sensitisation to fatal cells can be as high as 25% [21]. In the NICE guidance for management of ectopic pregnancy, the recommendation for anti-D is be used for those undergoing surgical management [22].

11. Role in pregnancy of unknown location (PUL)

The term pregnancy of unknown location is associated with the cases where there is a positive pregnancy test and no evidence of intra- or extrauterine pregnancies. Symptomatic cases requires surgical intervention. However asymptomatic cases represent a clinical challenge as It can be a falling extra or intra uterine pregnancies and resolve spontaneously in approximately 41–69% percent of the cases. Additional 30–37% evolves into visible intrauterine or extrauterine pregnancies. The reminder remains asymptomatic cases where the b-hCG fails to decline and does not evolve into either intrauterine or extrauterine [21]. These cases remains with no visible intrauterine or extrauterine pregnancies (by ultrasound and laparoscopy). Those cases can have the b-hCG sub optimally raising or remains static and are manageable with methotrexate. Regular follow up following methotrexate administration is recommended with b-hCG checks at day 1, day 4, day 7 and weekly after until the b-hCG falls below 15 iu [23, 24].

12. Role of methotrexate in ectopic post surgical management

Persistent trophoblast is identified by failure of b-hCG to decline after surgical treatment. It occurs more frequently in patients who are treated by salpingotomy (8%) compared to (less than 1%) in those treated by salpingectomy [25, 26]. Persistent trophoblast after salpingotomy can be managed expectantly or by administration of methotrexate. Methotrexate use provides higher and consistent success and shorter duration of follow ups in those cases compared to expectant management [25].

13. Role of methotrexate in challenging none-tubal ectopic pregnancies

Methotrexate has defined clear role in none tubal ectopic pregnancies where the surgical management is associated with very high morbidity with higher risk of bleeding and technical challenges. These situations include, scar ectopic, ovarian and abdominal ectopics, cervical ectopic pregnancy and interstitial (cornual) ectopic pregnancies [27, 28, 29].