Ectopic Pregnancy Treatment & Management

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potential risks of tubal rupture.

Approximately one fourth of women presenting with ectopic pregnancies have declining -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 -HCG titer also correlates with successful spontaneous resolution. Although

data are limited on this matter, initial -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 -HCG has been reported, making close follow-up and patientcompliance of paramount importance.

Methotrexate Therapy

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. [58]

Successful medical treatment using methotrexate has been reported in the literature with good subsequentreproductive outcomes. By avoiding surgery, the risk of tubal injury is reduced. [59]

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 betahuman chorionic gonadotropin (-HCG) level and ultrasonographic

identification of a gestational sac outside of the uterus

Abnormal doubling rate of the -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 act ivity 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

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

Contraindications

A -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.


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Although patients with -HCG levels above 5,000 IU/L and fetal cardiac act ivity 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 -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 -HCG is above 5,000

IU/L.[60]

Other contraindications to the use of methotrexate include the following :

Documented hypersensitivity to methotrexateBreastfeeding

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 -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 oftelephone 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


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method of contacting the physician or the hospital in case of emergency.

Methotrexate Treatment Protocols

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

Multiple-dose regimen

Initial experience used mult iple doses of methotrexate with leucovorin to minimize adverse effects. Leucovorin isfolinic 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 methotrexates 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. [8]

Day 0

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

Day 1

Obtain levels of the following:

-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 -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 -HCG and AST levels and perform a complete blood count (CBC). If the -HCG level has dropped 15% or

more since day 4, obtain weekly -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 -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


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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 -HCG level. Based on efficacy studies done by

Lipscomb et al, success exceeded 90% for single-dose methotrexate when -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-HCG level of greater than 15,000 mIU/mL. [7]

Before initiating therapy, draw blood to determine baseline laboratory values for renal, hepatic, and bone marrow

function, as well as a baseline -HCG level. Determine blood type, Rh factor, and the presence of antibodies.

Patients who are Rh negative should receive Rh immunoglobulin.

Obtain repeat -HCG levels 4 days and 7 days after the methotrexate inject ion. An initial increase in -HCG levels

often occurs by the third day and is not a cause for alarm. A decline in -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.[61] The patient's -HCG levels should be measured weekly, until they become undetectable.

Failure of medical treatment is defined when -HCG levels increase, plateau, or fail to decrease adequately by15% 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.

Investigational Medical Treatments

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.

Salpingostomy and Salpingectomy

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. 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 ofchoice 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).


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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.

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.)

Linear incision being made at the antimesenteric side of the ampullary portion of the fallopian tube.

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.)

Laparoscopic picture of an ampullary ectopic pregnancy protruding out after a linear salpingostomy w as perf ormed.

Schematic of a tubal gestation being teased out after linear salpingostomy.

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
http://refimgshow%289%29/


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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 ofthe 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 copiousirrigation 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.

Monitoring

After surgical excision of an ectopic gestation, weekly monitoring of quantitative betahuman chorionic


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gonadotropin (-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 -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 -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 -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 -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 -HCG levels. Further

medical treatment with methotrexate or surgery in symptomatic patients may be necessary if -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.

Contributor Information and DisclosuresAuthor

Vicken P Sepilian, MD, MSc Medical Director, Reproductive Endocrinology and Infertility , CHA Fertil ity

Center

Vicken P Sepilian, MD, MSc is a member of the following medical societies:American College of Obstetricians

and Gynecologists andAmerican Society for Reproductive Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Ellen Wood, DO, FACOOG Voluntary Assistant Professor, University of Miami, Leonard M Miller School of

Medicine

Ellen Wood, DO, FACOOG is a member of the following medical societies: American Society for Reproductive

Medicine


Chief Editor

Michel E Rivlin, MD Professor, Department of Obstetrics and Gynecology, University of Mississippi School of

Medicine

Michel E Rivlin, MD is a member of the following medical societies: American College of Obstetric ians and

Gynecologists,American Medical Association, Mississippi State Medical Association, Royal College ofObstetricians and Gynaecologists, and Royal College of Surgeons of Edinburgh


Additional Contributors

A David Barnes, MD, PhD, MPH, FACOG Consulting Staff, Department of Obstetrics and Gynecology,

Mammoth Hospital (Mammoth Lakes, California), Pioneer Valley Hospital (Salt Lake City, Utah), Warren

General Hospital (Warren, Pennsylvania), and Mountain West Hospital (Tooele, Utah)

A David Barnes, MD, PhD, MPH, FACOG is a member of the following medical societies:American College of

Forensic Examiners,American College of Obstetricians and Gynecologists,American Medical Association,

Association of Military Surgeons of the US, and Utah Medical Association


Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center

College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
http://www.utahmed.org/http://www.amsus.org/http://www.ama-assn.org/http://www.acog.org/http://www.acfei.com/http://www.rcsed.ac.uk/http://www.msmaonline.com/http://www.ama-assn.org/http://www.acog.org/http://www.asrm.org/http://www.asrm.org/http://www.acog.org/


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Disclosure: Medscape Salary Employment

Robert K Zurawin, MD Associate Professor, Director of Baylor College of Medicine Program for Minimally

Invasive Gynecology, Director of Fellowship Program, Minimally Invasive Surgery, Department of Obstetrics and

Gynecology, Baylor College of Medicine

Robert K Zurawin, MD is a member of the following medical societies:American Association of Gynecologic

Laparoscopists,American College of Obstetricians and Gynecologists,American Society for Reproductive

Medicine,Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and

Gynecologists, Harris County Medical Society, North American Society for Pediatric and AdolescentGynecology, and Texas Medical Association

Disclosure: Johnson and Johnson Honoraria Speaking and teaching; Conceptus Honoraria Speaking and

teaching; ConMed Consulting fee Consulting

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