Approach Considerations

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.

Expectant Management

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 betahuman chorionic gonadotropin (-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 -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 patient compliance 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. [64]

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.
[65]
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 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
-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.

Although patients with -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 -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. [66]

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 -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.