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ACOG Practice Bulletin on Methotrexate Treatment for Ectopic Pregnancy
1. ACOG Practice Bulletin No. 3 1
ACOG
PRACTICE
BULLETIN
CLINICAL MANAGEMENT GUIDELINES FOR
OBSTETRICIAN–GYNECOLOGISTS
NUMBER 3, DECEMBER 1998
(Replaces Technical Bulletin Number 150, December 1990)
This Practice Bulletin was
developed by the ACOG Com-
mittee on Practice Bulletins—
Gynecology with the assistance
of Steven J. Ory, MD. The in-
formation is designed to aid
practitioners in making deci-
sions about appropriate obste-
tric and gynecologic care.These
guidelines should not be con-
strued as dictating an exclusive
course of treatment or proce-
dure.Variations in practice may
be warranted based on the needs
of the individual patient, re-
sources, and limitations unique
to the institution or type of
practice.
Medical Management of
Tubal Pregnancy
Ectopic pregnancy is a major health problem for women of reproductive age
and, in the United States, is the leading cause of pregnancy-related death during
the first trimester. Diagnosis and treatment of tubal pregnancy before tubal rupture
occurs decreases the risk of death. Early detection may make it possible for
some patients to receive medical therapy instead of surgery. Methotrexate, a
folinic acid antagonist, has been used to treat patients with small unruptured
tubal pregnancies. The purpose of this document is to present evidence, including
risks and benefits, about methotrexate as an alternative treatment for selected
ectopic pregnancies.
Background
Incidence
The incidence of ectopic pregnancy has increased in the United States since
1970, the year the Centers for Disease Control (CDC; now the Centers for Disease
Control and Prevention) first began collecting data, when the rate was 4.5 per
1,000 reported pregnancies. In 1992, there were an estimated 108,800 ectopic
pregnancies, accounting for about 20 per 1,000 pregnancies and about 9% of all
pregnancy-related deaths (1). Current data do not include conditions diagnosed
and treated in physicians’ offices; therefore, the true incidence of ectopic preg-
nancy is probably underestimated.
Etiology
Prior pelvic inflammatory disease, especially that caused by Chlamydia tra-
chomatis, is the most important risk factor for ectopic pregnancy; observed odds
ratios range from 2.0 to 7.5 (2). Other factors that appear to be associated with an
increased risk of ectopic pregnancy include prior ectopic pregnancy, cigarette
2. 2 ACOG Practice Bulletin No. 3
smoking, prior tubal surgery (especially for distal tubal
disease), diethylstilbestrol exposure, and increasing age.
A history of infertility, independent of tubal disease,
and ovulation induction also appear to be risk factors for
ectopic pregnancy. Ectopic pregnancy is more likely to be
diagnosed early in patients being treated for infertility. Such
patients may be good candidates for medical therapy.
Effects of Therapy
Methotrexate is a folinic acid antagonist that inhibits
dihydrofolic acid reductase, interfering with DNA syn-
thesis, repair, and cellular replication.Actively proliferating
tissue such as malignant cells, bone marrow, fetal cells,
buccal and intestinal mucosa, and cells of the urinary
bladder generally are more sensitive to these effects of meth-
otrexate. Methotrexate has the potential for serious tox-
icity. Toxic effects usually are related to the amount
and duration of therapy, but toxicity has been seen even
with low doses. When methotrexate is used as a treatment
for ectopic pregnancy, most reported side effects have been
mild and self-limiting (3–12). This is probably a reflection
of the lower dosage and shortened duration of treatment
compared with dosages used in treating malignancies.
Diagnosis
Serial quantitative levels of the beta subunit of human
chorionic gonadotropin (β-hCG) can be used in combin-
ation with transvaginal ultrasonography and, in some cases,
suction curettage and serum progesterone measurements
to differentiate failed intrauterine pregnancy, threatened ab-
ortion, and intrauterine or ectopic pregnancies. A pre-
sumptive diagnosis of unruptured tubal ectopic pregnancy
is required before medical management can be considered.
Beta Subunit of Human Chorionic Gonadotropin
The mean plasma concentration of human chorionic
gonadotropin (hCG) is significantly lower for an ectopic
pregnancy than for a viable intrauterine pregnancy, but
there is no definitive laboratory level permitting distinc-
tion between the two. A consistently declining hCG level
indicates a nonviable pregnancy.
Conventionally, serial hCG testing to diagnose sus-
pected ectopic pregnancy is performed at 48-hour
intervals; a 66% or greater increase should be observed in
a normal pregnancy. Approximately 15% of normal intra-
uterine pregnancies are associated with less than a 66%
increase in hCG, and 17% of ectopic pregnancies have
normal doubling times (13). Limitations of serial hCG
testing include its inability to distinguish a failing intra-
uterine pregnancy from an ectopic pregnancy and the
inherent 48-hour delay. A prospective study of asymp-
tomatic patients described a 36% sensitivity and a 63–71%
specificity (14). However, most reports and clinicians have
found serial hCG testing useful in the early diagnosis of
ectopic pregnancy. The rate of hCG doubling decreases
from every 1.4–1.5 days in early pregnancy to every 3.3–
3.5 days at 6–7 weeks of gestation, at which point the
reliability of serial testing may be diminished.
The elimination of hCG after treatment of ectopic
pregnancy follows a two-phase distribution. The major
elimination has a half-life of 5–9 hours and a second, longer
phase has a half-life of 22–32 hours.
The quantitation of hCG has been complicated by the
existence of three different reference standards for hCG
assays, the existence of multiple antibodies in commercial
assays, and confusing nomenclature. These complicating
factors can cause varying and inconsistent results, both from
one laboratory to another and within the same laboratory,
and affect interpretation of the results and clinical manage-
ment.
Ultrasonography
Transvaginal ultrasonography often can detect intraut-
erine pregnancy within 5 weeks of the last menstrual period.
The concept of the discriminatory hCG zone, originally
applied to transabdominal ultrasonography, is the range of
serum hCG concentration above which a normal intra-
uterine gestation can be visualized consistently. When the
hCG level exceeds the discriminatory zone, the absence
of an intrauterine gestational sac is suggestive of ectopic
pregnancy, but this also can occur with multiple gestation
or failed intrauterine pregnancy. The specific discriminatory
zone varies with the hCG assay chosen, the reference
standard with which it is calibrated, and the available
ultrasound resolution. Findings also may be compromised
by obesity, fibroids, and the axis of the uterus. An intra-
uterine gestational sac in a normal uterus usually can be
seen with transvaginal ultrasonography when the hCG level
is between 1,000 to 2,000 mIU/mL (1st and 2nd Inter-
national Reference Preparation or IRP) (15, 16). If the
precise gestational age is known, as in the case of patients
receiving hCG for ovulation induction or oocyte retrieval,
the failure to detect a gestational sac 24 days or later after
conception is presumptive evidence of an abnormal preg-
nancy (13).
Historically, detection of an intrauterine sac has led to
the presumptive exclusion of ectopic pregnancy, based on
the estimate of the incidence of heterotopic pregnancy of 1
in 30,000. This figure was calculated almost 50 years ago
by multiplying the incidence of ectopic pregnancy by that
of dizygotic twinning, thus producing a hypothetical es-
timate. The incidence of heterotopic pregnancy appears to
have increased with the use of assisted reproductive tech-
niques. It has been reported to be as high as 1% in some
series (17), although the overall incidence of heterotopic
pregnancy is probably much lower.
3. ACOG Practice Bulletin No. 3 3
Clinical Considerations and
Recommendations
Who are candidates for medical management?
General factors to consider in determining candidates for
medical therapy include the size of the ectopic mass,
whether it has ruptured, and the desire for future fertility.
Patients should be hemodynamically stable without active
bleeding or signs of hemoperitoneum. Furthermore, they
should be willing and able to return for follow-up care.
Absolute and relative indications and contraindications to
medical therapy are shown in the boxes.
The identification of an ectopic gestational sac is
diagnostic of ectopic pregnancy, but it is not seen in all
cases. Sensitivity and specificity of transvaginal ultra-
sonography to identify ectopic pregnancy vary according
to criteria used for diagnosis. Reported sensitivity of
transvaginal ultrasonography ranges from 20.1% to 84%
and specificity from 98.9% to 100%, depending on the
criteria applied (18). Color flow Doppler may aid in the
diagnosis of ectopic pregnancy; however, it requires consid-
erably greater technical expertise (19, 20).
Serum Progesterone
Some clinicians maintain that measurement of serum
progesterone levels may be useful for distinguishing viable
intrauterine pregnancies from spontaneous abortions
and ectopic pregnancies, but serum progesterone levels
cannot distinguish ectopic pregnancy from spontaneous
abortion (21). There is no single progesterone value that
will definitively confirm the viability or nonviability of
an intrauterine pregnancy or the presence of an ectopic
pregnancy. Serum progesterone levels increase during
pregnancy (22). If the duration of the pregnancy is
unknown, interpretation of the test results is less reliable.
The use of ovulation-induction agents is associated with
higher serum progesterone levels in intrauterine and ec-
topic pregnancies.
Of pregnant patients with serum progesterone values
of less than 5 ng/mL, 85% have spontaneous abortions,
0.16% have viable intrauterine pregnancies, and 14% have
ectopic pregnancies (23). Pregnant patients with serum
progesterone levels between 20.0 and 24.9 ng/mL have
ectopic pregnancies in 4% of cases; 2% of ectopic pregnan-
cies occur with serum progesterone levels greater than 25
ng/mL. Most ectopic pregnancies (52%) are associated with
serum progesterone levels between 10 and 20 ng/mL, thus
limiting the clinical utility of this assessment (24).
The absence of products of conception on curettage in
the presence of an elevated β-hCG level is evidence of a
presumptive diagnosis of ectopic pregnancy. More rarely,
gestational trophoblastic disease, nongestational chorio-
carcinoma, or an embryonal cell tumor may be the cause.
Success Rates
Success is defined as resolution of the ectopic pregnancy
without surgical intervention. Reported success rates range
from 67% to 100%, with a median of 84% for the single-
dose methotrexate regimen (3–12). The largest study
involved 120 women and had an overall success rate of
94.1% (10). Variation in success rates may be affected by
the selection criteria and differences in management. Of
those cases with successful outcome, as many as 25%
required more than one dose of methotrexate (3, 6, 8, 25).
▲
Criteria for Receiving Methotrexate
Absolute indications
Hemodynamically stable without active bleeding
or signs of hemoperitoneum
Nonlaparoscopic diagnosis
Patient desires future fertility
General anesthesia poses a significant risk
Patient is able to return for follow-up care
Patient has no contraindications to methotrexate
Relative indications
Unruptured mass ≤3.5 cm at its greatest
dimension
No fetal cardiac motion detected
Patients whose β-hCG level does not exceed a
predetermined value (6,000–15,000 mIU/mL)
Contraindications to Medical Therapy
Absolute contraindications
Breastfeeding
Overt or laboratory evidence of immunodeficiency
Alcoholism, alcoholic liver disease, or other
chronic liver disease
Preexisting blood dyscrasias, such as bone
marrow hypoplasia, leukopenia, thrombocy-
topenia, or significant anemia
Known sensitivity to methotrexate
Active pulmonary disease
Peptic ulcer disease
Hepatic, renal, or hematologic dysfunction
Relative contraindications
Gestational sac ≥3.5 cm
Embryonic cardiac motion
4. 4 ACOG Practice Bulletin No. 3
How is methotrexate used in the medical man-
agement of tubal ectopic pregnancy?
Because injected methotrexate is a relatively new treatment
for ectopic pregnancy, a standardized protocol has yet to
be defined. There are small variations among the published
protocols, but all share a basic strategy. The differences
are in the amount of methotrexate given, the frequency of
follow-up visits, and the types of tests and procedures
routinely used to monitor treatment response.
Before methotrexate is injected, blood is drawn to
determine baseline laboratory values for renal, liver, and
bone marrow function, as well as to measure the β-hCG
level. Progesterone also may be measured. Blood type, Rh
factor, and the presence of antibodies should be determined.
Patients who are Rh negative receive Rh immune globulin.
The methotrexate dose usually is calculated according to
estimated body surface area (50 mg/m2
) and is given in
one dose. Treatment with a standard 75 mg dose (11) and
multiple serial doses with a folinic acid rescue on alternate
days (four doses of methotrexate [1.0 mg/kg] on days
0, 2, 4, and 6 and four doses of leucovorin [0.1 mg/kg] on
days 1, 3, 5, and 7) (26, 27) also have been successful.
Methotrexate is given either in divided doses, half into each
buttock, or in one intramuscular injection (3–12).
Follow-up care continues until β-hCG levels are
nondetectable. Time to resolution is variable and can be
protracted, taking a month or longer (3, 5, 6, 9, 10, 12).
With the single-dose regimen, levels of β-hCG usually
increase during the first several days following methotrexate
injection and peak 4 days after injection. If a treatment
response is observed, hCG levels should decline by 7 days
after injection (4, 10, 11). If the β-hCG level does not
decline by at least 15% from day 4 to day 7, the patient
may require either surgery (4), or a second dose of metho-
trexate if no contraindications exist (3, 5, 10–12). If there
is an adequate treatment response, hCG determinations
are reduced to once a week. An additional dose of metho-
trexate may be given if β-hCG levels plateau or increase
in 7 days (6–10). Surgical intervention may be required
for patients who do not respond to medical therapy. Ultra-
sound examination may be repeated to evaluate significant
changes in clinical status, such as increased pelvic pain,
bleeding, or inadequate declines of β-hCG levels (5, 6, 9,
10).
What are the potential problems associated with
medical management of ectopic pregnancy?
Potential problems can be divided into three categories:
1) drug-related side effects, 2) treatment-related com-
plications, and 3) treatment failure (see the box). If medical
therapy fails, additional treatment is required; in case of
tubal rupture, rapid surgical intervention is necessary. It is
Side Effects Associated with
Methotrexate Treatment
Drug side effects
Nausea
Vomiting
Stomatitis
Diarrhea
Gastric distress
Dizziness
Severe neutropenia (rare)
Reversible alopecia (rare)
Pneumonitis
Treatment effects
Increase in abdominal pain (occurs in up to two
thirds of patients)
Increase in β-hCG levels during first 1–3 days of
treatment
Vaginal bleeding or spotting
Signs of treatment failure and tubal rupture
Significantly worsening abdominal pain, regardless
of change in β-hCG levels
Hemodynamic instability
Levels of β-hCG that do not decline by at least
15% between day 4 and day 7 postinjection
Increasing or plateauing β-hCG levels after the first
week of treatment
▲
important, therefore, to monitor patients for signs and
symptoms of tubal rupture and treatment failure.
During treatment, patients should be counseled to
discontinue folinic acid supplements, including prenatal
vitamins. Because of its potential toxicity, patients receiving
methotrexate should be monitored carefully. Physicians
using this drug should be aware of potential side effects
and signs of toxicity and be advised to avoid the use of
nonsteroidal antiinflammatory drugs.
An initial increase in β-hCG levels often occurs by
the third day and is not a cause for alarm (4, 10, 11). Most
patients experience at least one episode of increased
abdominal pain sometime during treatment (5, 6, 9–11).
Because abdominal pain also is suggestive of tubal rupture,
care should be taken to evaluate any significant change in
discomfort. The pain associated with resolution of tubal
pregnancy usually can be distinguished from tubal rupture.
It generally is milder, of limited duration (24–48 hours),
▲
5. ACOG Practice Bulletin No. 3 5
and not associated with signs of an acute abdomen or
hemodynamic instability.
Medical treatment has failed when β-hCG levels either
increase or plateau by day 7 postinjection, indicating a
continuing ectopic pregnancy, or when the tube ruptures.
Tubal rupture may occur despite declining β-hCG levels
(6, 9, 10).
How should patients be counseled about im-
mediate and long-term effects of medical
therapy?
Patients should receive information about the types of side
effects they may experience and about activity restrictions
during treatment. They should be informed of the ongoing
risk of tubal rupture during treatment; it is important to
educate patients about symptoms of tubal rupture and
emphasize the need to seek immediate medical attention if
these symptoms occur (see the box).
It is difficult to assess the impact of methotrexate
treatment for ectopic pregnancy on a woman’s ability to
conceive. Published evidence regarding conception rates
following methotrexate administration is limited. One study
reported a 20% conception rate among 15 women, with a
mean follow-up time of 11.8 months (5). Another study
reported a significantly greater conception rate of 79.6%,
with a mean time to conception of 3.2 months (10); 12.8%
of the conceptions were recurrent ectopic pregnancies. The
impact of methotrexate on future fertility requires further
study.
How cost-effective is methotrexate treatment?
There is evidence that methotrexate therapy is a cost-
effective treatment for small unruptured ectopic pregnancies
when compared with laparoscopic salpingostomy. The
direct cost advantages are due to elimination of operating
room use, anesthesia services, and surgical fees. Indirect
costs decrease as a result of quicker recovery times;
however, the amount of savings depends on the proportion
of patients eligible to receive medical therapy and the
overall success rate. A study comparing direct costs of
methotrexate with laparoscopic salpingostomy found there
are significant savings if methotrexate is used as the primary
therapy (28). An additional study looked retrospectively at
patients treated for ectopic pregnancy and also found
methotrexate was cost-effective (29).
Is there ever a role for expectant management?
Distinguishing patients who are experiencing spontaneous
resolution of their ectopic pregnancies from patients who
have proliferating ectopic pregnancies and require active
intervention is a clinical dilemma. In patients who are
suspected to be undergoing spontaneous clinical resolution,
expectant management is an option that has been used in
the hope of avoiding therapy that might otherwise be
unnecessary. Candidates for successful expectant man-
agement must be willing to accept the potential risks of
tubal rupture and hemorrhage; they should be asympto-
matic and have objective evidence of resolution (generally
manifested by declining hCG levels). In general, patients
with early, small tubal gestations with lower hCG levels
are the best candidates for observant management. Ap-
proximately 20–30% of ectopic pregnancies are associated
with declining hCG levels at the time of presentation (30).
If the initial hCG level is less than 200 mIU/mL, 88% of
patients experience spontaneous resolution. Lower suc-
cess rates can be anticipated with higher hCG levels (31).
Reasons for abandoning expectant management include
intractable or significant increase in pain, failure of hCG
levels to decrease, and tubal rupture with hemoperitoneum.
Summary
The following recommendations are based on limited
or inconsistent scientific evidence (Level B):
Intramuscular methotrexate is an appropriate method
for treating selected patients with small, unruptured
tubal pregnancies.*
Successful treatment with methotrexate may require
more than one dose of methotrexate.*
Failure of β-hCG levels to decrease by at least 15%
from day 4 to day 7 after methotrexate administration
indicates the need for an additional dose of meth-
otrexate or surgery.*
▲
▲
▲
▲
▲
▲
Counseling Patients
Patients should be instructed on the following points:
To expect to experience one or more side effects,
including abdominal pain, vaginal bleeding or
spotting, or medication side effects
To contact the physician in the presence of sudden
onset of severe abdominal pain; substantial
increase in abdominal pain; heavy vaginal
bleeding; or dizziness, syncope, or tachycardia
To avoid alcoholic beverages, vitamins containing
folic acid, nonsteroidal antiinflammatory drugs,
and sexual intercourse until advised otherwise
*
Evidence is limited but consistent.
6. 6 ACOG Practice Bulletin No. 3
The following recommendation is based primarily
on consensus and expert opinion (Level C):
There may be a role for expectant management of
hemodynamically stable patients with presumptive
ectopic pregnancy in whom β-hCG levels are low
(<200 mIU/mL) and declining.
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