Ectopic Pregnancy: Diagnosis and Management

Jennifer L Kulp; Kurt T Barnhart


Women's Health. 2008;4(1):79-87. 

In This Article


Medical Management

Methotrexate is a folic acid antagonist. It works by inhibiting the synthesis of purines and pyrimides and therefore interfering with DNA synthesis. Methotrexate affects rapidly dividing cells and halts mitosis. In ectopic gestations, it prevents the proliferation of the cytotrophoblasts. This results in decreased trophoblast ß-hCG production, which causes decreased secretion of progesterone by the corpus luteum.

In the 1980s, methotrexate was first used to treat ectopic pregnancies. A study by Stovall et al., published in 1989, described outpatient treatment of ectopic pregnancy with methotrexate. In this protocol, a leucovorine 'rescue' was used.[23] Leucovorine is folinic acid and allows a higher dose of methotrextate to be used by mitigating some of its side effects. In this protocol, which is known as the multiple-dose methotrexate protocol, methotrexate is given at a dose of 1 mg/kg intramuscularly on days 1, 3, 5 and 7. Leucovorine is given at a dose of 0.1 mg/kg intramuscularly on days 2, 4, 6 and 8. In the multidose protocol, up to four doses of methotrexate are given until ß-hCG levels decrease by 15% on two consecutive days ( Table 2 ). ß-hCG levels are followed weekly until they are less than 15 IU/L. A second course of methotrexate may be given after 1 week if ß-hCG levels increase or plateau. The study by Stovall et al. reported a success rate of 90% using this protocol ( Table 2 ).[23]

A single-dose protocol was developed subsequently. It was noted in prior studies that giving a single-dose of methotrexate might enhance patient compliance without decreasing effectiveness. Therefore, the protocol came to be known as the single-dose methotrexate protocol, as most patients only receive a single dose of the medication. In this protocol, methotrexate is given at a dose of 50 mg/m2 on day 1. A second dose is given on day 7 if ß-hCG values do not decrease by at least 15% between days 4 and 7. ß-hCG levels are followed weekly until they are undetectable (see Table 2 ). An article by Lipscomb et al. reported that 20% of patients undergoing this protocol will require more than one treatment cycle.[24] The mean time to resolution of the ectopic pregnancy was 35 days but could take as long as 109 days. There is no leucovorin rescue used in this protocol. After initial diagnosis, ultrasounds are generally not repeated. The ectopic gestation may actually increase in size after methotrexate treatment, which may be due to hematoma formation.

Prior to giving methotrexate, a complete blood count, liver function tests and creatinine should be checked. In a patient with a history of pulmonary disease, a chest x-ray should be obtained owing to the risk of interstitial pneumonitis with methotrexate therapy. Absolute contraindications to methotrexate therapy are a hemodynamically unstable patient, a patient who is breastfeeding, has immunodeficiency, liver disease or alcoholism, active pulmonary disease, peptic ulcer disease and hematologic, renal or liver dysfunction. Relative contraindications are an ectopic gestation 3.5 cm in size or greater and the presence of fetal heart activity.[25] These contraindications are related to the efficacy of methotrexate as well as its side effects. Methotrexate is generally well tolerated in doses given to treat ectopic pregnancy. High-dose methotrexate has been associated with bone marrow suppression, hepatotoxicity, stomatitis, pulmonary fibrosis, reversible alopecia, photosensitivity and febrile morbidity. The most common side effect is mild elevations of liver transaminases. Patients receiving methotrexate should stop prenatal vitamins or folic acid supplements.

During treatment with methotrexate, ß-hCG levels may actually rise or plateau between days 1 and 4 before they start to decrease. This is thought to be due to the syncytiotrophoblasts that continue to produce ß-hCG after methotrexate treatment. Another phenomenon seen during treatment with methotrexate is transient abdominal pain, which can occur 3-7 days after the start of therapy and can last for 4-12 h. This can be due to a tubal bleed, the formation of a hematoma or a tubal abortion. It is also important to rule out tubal rupture, which would be an indication for surgical intervention. Clinical indications for surgery are abdominal pain that is severe and persistent beyond 12 h, orthostatic hypotension or decreasing hematocrit values.

Beyond the clinical signs of treatment failure, other signs indicating possible methotrexate failure include an increase or plateau of ß-hCG, which occurs after the first week of treatment.[25]

The effectiveness of different methotrexate protocols has been investigated. In 12 studies, which included 338 patients who underwent variable-dosing methotrexate therapy, in which therapy was titrated according to ß-hCG levels, the success rate of methotrexate therapy was 93%.[26] Furthermore, on follow-up hysterosalpingogram (HSG), fallopian tubal patency was 75%. The subsequent fertility rate was 58% and 7% of patients had a repeat ectopic pregnancy. In 32 studies of 1626 patients undergoing conservative laparoscopic surgery for ectopic pregnancy, both success rates and subsequent fertility rates were similar. This compares with seven studies of 393 patients who underwent the single-dose methotrexate protocol, with 87% having a successful resolution of the ectopic pregnancy. Of these patients, 8% required a second dose of methotrexate. Follow-up HSG demonstrated tubal patency in 81% of patients. Of patients desiring fertility, 61% subsequently had a demonstrated intrauterine pregnancy and 8% had a repeat ectopic pregnancy.[26] This suggests decreased efficacy of the single-dose methotrexate protocol as compared with the multidose protocol, while efficacy of the multidose methotrexate protocol is similar to that of conservative laparscopic surgery.

In another trial of 100 patients comparing methotrexate therapy with laparoscopic salpingostomy, 86% of patients receiving one or two doses of methotrexate were successfully treated. In patients undergoing laparoscopic salpingostomy, 72% were successfully treated with surgery alone and 20% required postoperative methotrexate for persistent trophoblast. Post-treatment tubal patency rates were similar in both medically and surgically treated patients.[27] A study by Dias Pereira et al. looked at fertility outcomes in 74 women desiring pregnancy who had undergone either multidose methotrexate therapy or laparoscopic salpingostomy for ectopic pregnancy and found pregnancy rates at 18 months to be 36 and 43%, respectively.[28] Post-treatment fertility rates do not appear to be different in patients undergoing medical or surgical management of ectopic pregnancy.

A meta-analysis by Barnhart et al., which looked at 26 studies and compared single- to multi-dose methotrexate protocols, found that use of the single-dose methotrexate protocol was associated with significantly greater failure rates. When baseline ß-hCG levels and the presence of fetal cardiac activity were controlled for, the single-dose methotrexate therapy had an almost five-times greater failure rate (OR: 4.75).[29]

Small studies have proposed that the success rates for medical management of ectopic pregnancy with single- and multi-dose are comparable.[30,31] However, small studies are underpowered and often lead to a type 2 error: not rejecting the null hypothesis that two therapies are different when in fact they are. In aggregate, treatment failure with single dose is a least 50% higher than multidose (RR: 1.5; 95% CI: 0.44-5.01) and as much as 135% higher when evaluating studies published after the meta-analysis (OR: 2.35; 95% CI: 0.92-7.70; p = 0.06).[32,33]

Given the lower success rate of the single-dose methotrexate protocol, a two-dose methotrexate protocol was developed in the hope of having a more effective regimen that was not too burdensome. In this protocol, the first dose of methotrexate is given on day 1 and a second dose is given on day 4. A third dose is given on day 7 only if the ß-hCG level did not decrease by 15% between day 4 and day 7 (see Table 2 ). This protocol does not require any more office visits than the single-dose protocol, yet gives two doses of methotrexate in the first week of the protocol. The two-dose methotrexate protocol was demonstrated to be safe and well tolerated in a study of 100 patients.[34] Further studies are needed to determine overall success rates.

Several pretreatment characteristics have been studied to determine if they affect the success rates of methotrexate treatment; specifically, ß-hCG level on presentation, progesterone level, size of gestation, the presence or absence of fetal cardiac activity and the presence of free blood in the pelvis. A study by Lipscomb et al. of 360 women looked at certain pretreatment characteristics of patients and correlated them with treatment success rates. The only one found to be significant on regression analysis success was initial ß-hCG level, with a large decrease in successful treatment (68.2%) seen in patients with ß-hCG levels at presentation of greater than 15,000 mIU/ml. The presence of fluid in the peritoneal cavity or size of the ectopic gestation was not associated with a decreased success rate.[35] A more recent study demonstrated that initial ß-hCG levels of greater than 5000 mIU/ml are associated with significantly decreased success rates for women treated with the single-dose protocol.[36]


The traditional surgery performed for an ectopic pregnancy was an exploratory laparotomy with salpingectomy. Today, many patients with ectopic pregnancies that require surgical management are treated with a laparoscopic salpingectomy or salpingostomy. However, if a patient presents in hypovolemic shock with a ruptured ectopic pregnancy, laparotomy and salpingectomy remain the treatment of choice.

Laparoscopy has the benefits of shorter hospital stay, shorter postoperative recovery time and being less expensive compared with laparotomy. We would be more likely to perform a laparoscopic salpingectomy instead of a salpingostomy in the following circumstances: uncontrolled bleeding, recurrent ectopic pregnancy in the same fallopian tube, an ectopic gestation greater than 5 cm or a severely damaged fallopian tube. In other cases, a salpingostomy may be appropriate. A longitudinal incision should be made on the antimesenteric border of the fallopian tube. This can be performed with a unipolar needle. The products of conception should then be removed from the fallopian tube by flushing with high-pressure irrigation. Any bleeding from the fallopian tube can be controlled with the use of electrosurgical fulguration. The incision on the fallopian tube can heal by secondary intention or can be sutured closed.

In a review of nine studies comparing laparoscopic salpingostomy with salpingectomy, there was not a significant difference in subsequent intrauterine pregnancy rate (approximately 50%). However there was an increased rate of repeat ectopic pregnancy in the salpingostomy group (10 vs 15%).[37] Another study suggests that there may be a higher subsequent fertility rate in patients undergoing salpingostomy instead of salpingectomy.[38]

After 5-20% of salpingostomies performed for ectopic pregnancies, there is persistent trophoblastic tissue.[39,40,41] All patients undergoing salpingostomy need to be followed with weekly ß-hCG levels until they are undetectable because of this risk. If ß-hCG levels plateau or increase, a persistent ectopic pregnancy is diagnosed. This may be treated with methotrexate. There is an increased risk of persistent ectopic pregnancy if the salpingostomy was performed at a very early gestational age, if the size of the ectopic pregnancy was less than 2 cm or in patients with high initial ß-hCG levels.[42]


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