Ectopic Pregnancy Treatment & Management

Among the greatest advances in the management of ectopic pregnancy has been the development of medical management, which became available in the mid-1980s. Initial protocols for medical therapy required long-term hospitalization and multiple doses of methotrexate and were associated with significant side effects. Modification and refinement of these protocols, however, have led to single-dose outpatient therapy.

Medical versus surgical therapy

Historically, the treatment of ectopic pregnancy was limited to surgery. With evolving experience with methotrexate, the treatment of selected ectopic pregnancies has been revolutionized. Medical therapy of ectopic pregnancy is appealing over surgical options for a number of reasons, including eliminating morbidity from surgery and general anesthesia, potentially less tubal damage, and less cost and need for hospitalization.

Measures of current trends in the management of ectopic pregnancy in the United States from 2002 to 2007 indicated that the percentage of patients treated with methotrexate increased from 11.1% to 35.1%, whereas surgical management decreased from approximately 90% to 65%. ^[4] In this study, the authors reported that more than 60% of surgical cases were done laparoscopically and that about 5% of surgical cases required medical therapy. In the medical treatment group, 15% of cases were categorized as failures and required surgery. ^[4]

Consultations

An obstetrics specialist should be consulted as needed for ectopic pregnancies and for follow-up care of patients with failing/failed intrauterine pregnancies or pregnancies of unknown location. Any patient who is clinically unstable should have the consultation in the emergency department. Furthermore, an obstetrics specialist or a radiologist should be consulted for transvaginal ultrasonography as needed, according to institutional policy.

The increased incidence of ectopic pregnancy is partially attributed to improved ability in making earlier diagnosis. Ectopic pregnancies that previously would have resulted in tubal abortion or complete, spontaneous reabsorption and remained clinically undiagnosed are now detected.

Some investigators have questioned the need for unnecessary surgical or medical intervention in very early cases and have advocated expectant management in select cases. However, distinguishing patients who are experiencing spontaneous resolution of their ectopic pregnancies from patients who have proliferative ectopic pregnancies could pose a clinical dilemma.

Candidates for successful expectant management should be asymptomatic and have no evidence of rupture or hemodynamic instability. Furthermore, they should demonstrate objective evidence of resolution, such as declining beta–human chorionic gonadotropin (β-HCG) levels. They must also be fully compliant and be willing to accept the potential risks of tubal rupture.

Approximately one fourth of women presenting with ectopic pregnancies have declining β-HCG levels, and 70% of this group experience successful outcomes with close observation, as long as the gestation is 4cm or less in its greatest dimension. An initial low β-HCG titer also correlates with successful spontaneous resolution. Although data are limited on this matter, initial β-HCG titers below 1000 mIU/mL have been demonstrated to predict a successful outcome in 88% of cases managed expectantly.

Note that no cutoff value below which expectant management is uniformly safe has been established. Furthermore, rupture despite low and declining serum levels of β-HCG has been reported, making close follow-up and patient compliance of paramount importance.

Methotrexate is an antimetabolite chemotherapeutic agent that binds to the enzyme dihydrofolate reductase, which is involved in the synthesis of purine nucleotides. This interferes with deoxyribonucleic acid (DNA) synthesis and disrupts cell multiplication.

Methotrexate has long been known to be effective in the treatment of leukemias, lymphomas, and carcinomas of the head, neck, breast, ovary, and bladder. It has also been used as an immunosuppressive agent in the prevention of graft versus host disease and in the treatment of severe psoriasis and rheumatoid arthritis.

The effectiveness of methotrexate on trophoblastic tissue has been well established and is derived from experience gained in using this agent in the treatment of hydatiform moles and choriocarcinomas. As used in the treatment of ectopic pregnancy, methotrexate is administered in a single or in multiple intramuscular (IM) injections.

Treatment with methotrexate is an especially attractive option when the pregnancy is located on the cervix or ovary or in the interstitial or the cornual portion of the tube. Surgical treatment in these cases is often associated with increased risk of hemorrhage, often resulting in hysterectomy or oophorectomy.

In a study by Verma et al, only 1 of 64 cervical, cornual, or cesarean delivery scar pregnancies treated with systemic methotrexate alone or combined with intracardiac injection required surgery. ^[65]

Successful medical treatment using methotrexate has been reported in the literature with good subsequent reproductive outcomes. By avoiding surgery, the risk of tubal injury is reduced. ^[66]

Indications

Medical therapy for ectopic pregnancy involving methotrexate may be indicated in certain patients. To determine acceptable candidates for methotrexate therapy, first establish the diagnosis by one of the following criteria:

• Abnormal doubling rate of the beta–human chorionic gonadotropin (β-HCG) level and ultrasonographic identification of a gestational sac outside of the uterus

• Abnormal doubling rate of the β-HCG level, an empty uterus, and menstrual aspiration with no chorionic villi

A number of other factors must also be considered once the diagnosis is established, as follows:

• The patient must be hemodynamically stable, with no signs or symptoms of active bleeding or hemoperitoneum (must be met by every patient)

• The patient must be reliable, compliant, and able to return for follow-up care (must be met by every patient)

• The size of the gestation should not exceed 4cm at its greatest dimension (or exceed 3.5 cm with cardiac activity) on ultrasonographic measurement - Exceeding this size is a relative, but not absolute, contraindication to medical therapy

• Absence of fetal cardiac activity on ultrasonographic findings - The presence of fetal cardiac activity is a relative contraindication

• No evidence of tubal rupture - Evidence of tubal rupture is an absolute contraindication

• β-HCG level less than 5000 mIU/mL - Higher levels are a relative contraindication

A study by Bonin et al examined the records of 400 women who received methotrexate for ectopic pregnancy and concluded that predictive factors for successful methotrexate treatment include an initial hCG value < 1000IU/l and favorable early HCG kinetics and that predictive factors of treatment failure include hematosalpinx and pretherapeutic blood progesterone >5ng/ml at diagnosis. ^[67]

Contraindications

A β-HCG level of greater than 5,000 IU/L, fetal cardiac activity, and free fluid in the cul-de-sac on ultrasonographic images (presumably representing tubal rupture) are contraindications to medical therapy with methotrexate.

Although patients with β-HCG levels above 5,000 IU/L and fetal cardiac activity have been treated successfully with methotrexate, these patients require much greater surveillance and carry a higher risk of subsequent operative intervention. There is an inverse association between β-HCG levels and successful medical management of an ectopic pregnancy. A systematic review by Menon et al confirmed that there is a substantial increase in failure of medical management of ectopic pregnancy with single-dose methotrexate when the initial β-HCG is above 5,000 IU/L. ^[68]

Other contraindications to the use of methotrexate include the following :

• Documented hypersensitivity to methotrexate

• Breastfeeding

• Immunodeficiency

• Alcoholism

• Alcoholic liver disease

• Any other type of liver disease

• Blood dyscrasias

• Leukopenia

• Thrombocytopenia

• Anemia

• Active pulmonary disease

• Peptic ulcer disease

• Renal, hepatic, or hematologic dysfunction

Adverse effects and mandatory patient counseling

Adverse effects associated with the use of methotrexate can be divided into adverse drug effects and treatment effects. Adverse drug effects include the following:

• Nausea

• Vomiting

• Stomatitis

• Diarrhea

• Gastric distress

• Dizziness

Transient elevation in liver enzymes is also known to occur. Serious reactions such as bone marrow suppression, dermatitis, pleuritis, pneumonitis, and reversible alopecia can occur with higher doses but are rare with doses used in the treatment of ectopic pregnancy.

Treatment effects of methotrexate include an increase in abdominal pain (occurring in up to two thirds of patients), an increase in β-HCG levels during the first 1-3 days of treatment, and vaginal bleeding or spotting.

The medical treatment of ectopic pregnancy requires compulsive compliance. The physician must emphasize the importance of patient follow-up and have patient information on hand, including the patient's home address, telephone numbers at home and work, and the means to reach a contact person in case attempts to reach the patient directly are unsuccessful. Proper documentation of attempts to reach the patient, including records of telephone calls and certified mail are important medical-legal considerations.

Before injection of methotrexate, the patient must be counseled extensively on the risks, benefits, and adverse effects of the treatment and on the possibility of failure of medical therapy, which would result in tubal rupture and necessitate surgery. Patients should be aware of the signs and symptoms associated with tubal rupture, and they should be advised to contact their physician with significantly worsening abdominal pain or tenderness, heavy vaginal bleeding, dizziness, tachycardia, palpitations, or syncope.

Most patients experience at least 1 episode of increased abdominal pain, which usually occurs 2-3 days after the injection. Increased abdominal pain is believed to be caused by the separation of the pregnancy from the implanted site. It can be differentiated from tubal rupture in that it is milder, of limited duration (lasting 24-48 h), and is not associated with signs of acute abdomen or hemodynamic instability.

Advise patients to avoid alcoholic beverages, vitamins containing folic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), and sexual intercourse, until advised otherwise. A signed written consent demonstrating the patient's comprehension of the course of treatment must be obtained. Provide an information pamphlet to all patients receiving methotrexate; the pamphlet should include a list of adverse effects, a schedule of follow-up visits, and a method of contacting the physician or the hospital in case of emergency.

A number of accepted protocols with injected methotrexate exist for the treatment of ectopic pregnancy.

Multiple-dose regimen

Initial experience used multiple doses of methotrexate with leucovorin to minimize adverse effects. Leucovorin is folinic acid that is the end product of the reaction catalyzed by dihydrofolate reductase, the same enzyme inhibited by methotrexate. Normal dividing cells preferentially absorb leucovorin; hence, it decreases the action of methotrexate, thereby decreasing methotrexate’s adverse systemic effects.

This regimen involves administration of methotrexate as 1 mg/kg IM on days 0, 2, 4, and 6, followed by 4 doses of leucovorin as 0.1 mg/kg on days 1, 3, 5, and 7. Because of a higher incidence of adverse effects and the increased need for patient motivation and compliance, the multiple dosage regimen has fallen out of favor in the United States.

Single-dose regimen

The more popular regimen today is the single-dose injection, which involves injection of methotrexate as 50 mg/m² IM in a single injection or as a divided dose injected into each buttock. Studies comparing the multiple methotrexate dosage regimen with the single dosage regimen have demonstrated that the 2 methods have similar efficacy. With smaller dosing and fewer injections, fewer adverse effects are anticipated, and the use of leucovorin can be abandoned.

The protocol for single-dose methotrexate is detailed below. Using this protocol, Stovall et al achieved a 96% success rate with a single injection of methotrexate. ^[6]

Day 0

Obtain β-HCG level, ultrasonography, and +/- dilatation and curettage.

Day 1

Obtain levels of the following:

• β-HCG

• Liver function - Eg, aspartate aminotransferase (AST or serum glutamic-oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT or serum glutamic-pyruvic transaminase [SGPT])

• Blood urea nitrogen (BUN)

• Creatinine

Evidence of hepatic or renal compromise is a contraindication to methotrexate therapy. Blood type, Rh status, and antibody screening are also performed, and all Rh-negative patients are given Rh immunoglobulin.

Methotrexate (50 mg/m²) is administered by IM injection. Advise patients not to take vitamins with folic acid until complete resolution of the ectopic pregnancy. They should also refrain from alcohol consumption and intercourse for the same period.

Day 4

The patient returns for measurement of her β-HCG level. The level may be higher than the pretreatment level. The day-4 hCG level is the baseline level against which subsequent levels are measured.

Day 7

Draw β-HCG and AST levels and perform a complete blood count (CBC). If the β-HCG level has dropped 15% or more since day 4, obtain weekly β-HCG levels until they have reached the negative level for the lab. If the weekly levels plateau or increase, a second course of methotrexate may be administered.

If the β-HCG level has not dropped at least 15% from the day-4 level, administer a second IM dose of methotrexate (50 mg/m²) on day 7, and observe the patient similarly. If no drop has occurred by day 14, surgical therapy is indicated.

If the patient develops increasing abdominal pain after methotrexate therapy, repeat a transvaginal ultrasonographic scan to evaluate for possible rupture.

Treatment monitoring protocols

The best predictor of success of medical therapy is the initial β-HCG level. Based on efficacy studies done by Lipscomb et al, success exceeded 90% for single-dose methotrexate when β-HCG levels were less than 5000 mIU/mL but dropped to about 80% when levels were 5-10,000 mIU/mL. Success was less than 70% with an initial β-HCG level of greater than 15,000 mIU/mL. ^[5]

Before initiating therapy, draw blood to determine baseline laboratory values for renal, hepatic, and bone marrow function, as well as a baseline β-HCG level. Determine blood type, Rh factor, and the presence of antibodies. Patients who are Rh negative should receive Rh immunoglobulin.

Obtain repeat β-HCG levels 4 days and 7 days after the methotrexate injection. An initial increase in β-HCG levels often occurs by the third day and is not a cause for alarm. A decline in β-HCG levels of at least 15% from days 4 to 7 postinjection indicates a successful medical response. Other effective monitoring protocols have also been reported. ^[69] The patient's β-HCG levels should be measured weekly, until they become undetectable.

Failure of medical treatment is defined when β-HCG levels increase, plateau, or fail to decrease adequately by 15% from days 4 to 7 postinjection. At this time, surgical intervention may be warranted. A repeat single dose of methotrexate can also be a viable option after reevaluation of the patients' indications and contraindications (including repeat ultrasonography) for medical therapy.

The use of oral methotrexate is under investigation; although preliminary reports show promising results, efficacy remains to be established. Direct local injection (salpingocentesis) of methotrexate into the ectopic pregnancy under laparoscopic or ultrasonographic guidance has also been reported in the literature; however, these studies have yielded inconsistent results, and the advantage of this technique over IM injection remains to be established.

Although methotrexate has remained the most effective and popular drug used in medical therapy for an ectopic pregnancy, other protocols have been used, such as potassium chloride, hyperosmolar glucose, mifepristone (RU 486), and prostaglandins, and these agents have been administered orally, systemically, and locally into the ectopic pregnancy directly. These therapies remain experimental at present because the efficacy of such treatments, as well as their advantage over standard methotrexate protocol, has not been established.

Within the last 2 decades, a more conservative surgical approach to unruptured ectopic pregnancy using minimally invasive surgery has been advocated to preserve tubal function. The conservative approaches include linear salpingostomy and milking the pregnancy out of the distal ampulla. The more radical approach includes resecting the segment of the fallopian tube that contains the gestation, with or without reanastomosis.

Laparoscopy has become the recommended approach in most cases. ^[61] Laparotomy is usually reserved for patients who are hemodynamically unstable or for patients with cornual ectopic pregnancies; it also is a preferred method for surgeons inexperienced in laparoscopy and in patients in whom a laparoscopic approach is difficult (eg, secondary to the presence of multiple dense adhesions, obesity, or massive hemoperitoneum).

Multiple studies have demonstrated that laparoscopic treatment of ectopic pregnancy results in fewer postoperative adhesions than laparotomy. Furthermore, laparoscopy is associated with significantly less blood loss and a reduced need for analgesia. Finally, laparoscopy reduces cost, hospitalization time, and convalescence period.

Linear salpingostomy along the antimesenteric border to remove the products of conception is the procedure of choice for unruptured ectopic pregnancies in the ampullary portion of the tube. Ectopic pregnancies in the ampulla are usually located between the lumen and the serosa and, thus, are ideal candidates for linear salpingostomy. Several studies have demonstrated no benefit of primary closure (salpingotomy) over healing by secondary intention (salpingostomy).

Total salpingectomy is the procedure of choice in a patient who has completed childbearing and no longer desires fertility, in a patient with a history of an ectopic pregnancy in the same tube, or in a patient with severely damaged tubes.

In cases involving uncontrolled bleeding and hemodynamic instability, conservative treatment methods are avoided in favor of radical surgery.

A systematic review and meta-analysis compared the fertility outcomes of salpingectomy with those of salpingostomy among patients treated for tubal ectopic pregnancies. The two randomized, controlled trials included in the review showed no difference in the odds of a subsequent intrauterine pregnancy between salpingectomy and salpingostomy. However, in the 16 cohort studies that were reviewed, the likelihood of a subsequent intrauterine pregnancy was lower in patients who underwent salpingectomy. ^[70]

Linear salpingostomy

In linear salpingostomy, the involved tube is identified and freed from surrounding structures. To minimize bleeding, a dilute solution containing 20 U of vasopressin in 20 mL of isotonic sodium chloride solution may be injected into the mesosalpinx just below the ectopic pregnancy. Make sure that the needle is not in a blood vessel by aspirating before injecting, because intravascular injection of vasopressin may precipitate acute arterial hypertension and bradycardia.

Next, using a microelectrode, scissors, harmonic scalpel, or laser, a 1- to 2-cm linear incision is made along the antimesenteric side of the tube along the thinnest segment of the gestation. (See the image below.)

At this time, the pregnancy usually protrudes out of the incision and may slip out of the tube. Occasionally, it must be teased out using forceps or aqua-dissection, which uses pressurized irrigation to help dislodge the pregnancy. (See the images below.)

Coagulation of oozing areas may be necessary and can be accomplished using microbipolar forceps. Some ampullary pregnancies can be teased out and expressed through the fimbrial end (milking of the tube) by using digital expression, suction, or aqua-dissection. However, this approach carries with it a higher rate of bleeding, persistent trophoblastic tissue, tubal damage, and recurrent ectopic pregnancy (33%).

Segmental tubal resection and total salpingectomy

In some cases, resection of the tubal segment containing the gestation or a total salpingectomy is preferred over salpingostomy. This is true for isthmic pregnancies, in which the endosalpinx is usually damaged. These patients do poorly with linear salpingostomy, with a high rate of recurrent ectopic pregnancy occurring.

Segmental tubal resection is performed by grasping the tube at the proximal and distal borders of the segment of the tube containing the gestation and coagulating thoroughly from the antimesenteric border to the mesosalpinx. This portion of the tube is then excised. The underlying mesosalpinx is also coagulated and excised, with particular attention to minimize the damage to the surrounding vasculature.

Delayed microsurgical reanastomosis can be performed to reestablish tubal patency if enough healthy fallopian tube is present. Take care to minimize the thermal injury to the tube during excision, so that an adequate portion of healthy tube remains for the reanastomosis.

Total salpingectomy can be achieved by progressively coagulating and cutting the mesosalpinx, starting from the fimbriated end and advancing toward the proximal isthmic portion of the tube. At this point, the tube is separated from the uterus by coagulating and excising with scissors or laser.

Preoperative details

The optimal surgical management for a patient with an ectopic pregnancy depends on several factors, including the following:

• Patient's age, history, and desire for future fertility

• History of previous ectopic pregnancy or pelvic inflammatory disease (PID)

• Condition of the ipsilateral tube - Ie, ruptured or unruptured

• Condition of the contralateral tube - Eg, adhesions, tubal occlusion

• Location of the pregnancy - Ie, interstitium, ampulla, isthmus

• Size of the pregnancy

• Presence of confounding complications

In a patient who has completed childbearing and no longer desires fertility, in a patient with a history of an ectopic pregnancy in the same tube, or in a patient with severely damaged tubes, total salpingectomy is the procedure of choice. The presence of uncontrolled bleeding and hemodynamic instability warrants radical surgery over conservative methods. The preferred approach based on the location of the pregnancy varies, as previously discussed. In all instances, regardless of desired fertility, fully inform the patient of the possibility of a laparotomy with bilateral salpingectomy.

Intraoperative details

Throughout the procedure, take care to minimize blood loss and reduce the potential for retained trophoblastic tissue, which can reimplant and persist. Remove large gestations in an endoscopic bag, and perform copious irrigation and suctioning to remove any remaining fragments. Inspect the peritoneal cavity and remove any detected residual trophoblastic tissue.

Note the condition of the contralateral tube, the presence of adhesions, or other pathologic processes because this helps in the postoperative counseling of the patient with regard to future fertility potential.

Postoperative details

Proper pain control and hemodynamic stability are important postoperative considerations. Most often, patients treated with laparoscopy are discharged on the same day of surgery; however, overnight admission may be necessary for some patients in order to monitor postoperative bleeding and achieve adequate pain control. Patients treated by laparotomy are usually hospitalized for a few days.

After surgical excision of an ectopic gestation, weekly monitoring of quantitative beta–human chorionic gonadotropin (β-HCG) levels is necessary until the level is zero to ensure that treatment is complete. This is especially true following treatment with conservative surgery, ie, salpingostomy, which carries a 5-15% rate of persistent trophoblastic tissue. The average time for β-HCG to clear the system is 2-3 weeks, but up to 6 weeks can be required.

After tubal-sparing surgical removal of an ectopic pregnancy, a fall in β-HCG levels of less than 20% every 72 hours represents incomplete treatment. Although most of these cases are caused by incomplete removal of trophoblastic tissue, some actually may represent multiple ectopic pregnancies in which only 1 gestation is initially recognized and treated.

The incidence of persistent trophoblastic tissue is greater with higher initial β-HCG levels and is relatively rare with titers of less than 3000 IU/L. The risk of persistent trophoblastic tissue is very significant when a hematosalpinx is greater than 6cm in diameter, a β-HCG titer is more than 20,000 IU/L, and a hemoperitoneum is greater than 2 L.

While resolution without any further intervention is the general rule, the persistence of trophoblastic tissue has been associated with tubal rupture and hemorrhage even in the presence of declining β-HCG levels. Further medical treatment with methotrexate or surgery in symptomatic patients may be necessary if β-HCG levels do not decline or persist. Some authors have suggested administration of a prophylactic dose of methotrexate after conservative surgery to reduce the risk of persistent ectopic pregnancy.