Ectopic Pregnancy - Methotrexate Therapy - UpToDate

10/7/2019 Ectopic pregnancy: Methotrexate therapy - UpToDate
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Ectopic pregnancy: Methotrexate therapy

Author: Togas Tulandi, MD, MHCM
Section Editor: Courtney A Schreiber, MD, MPH
Deputy Editor: Sandy J Falk, MD, FACOG
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2019. | This topic last updated: May 14, 2019.
INTRODUCTION
An ectopic pregnancy is a pregnancy outside of the uterine cavity. The majority of ectopic
pregnancies occur in the fallopian tube (96 percent) [1], but other possible sites include cervical,
interstitial (also referred to as cornual; a pregnancy located in the proximal segment of the
fallopian tube that is embedded within the muscular wall of the uterus), hysterotomy scar (eg, in a
women with a previous cesarean delivery), intramural, ovarian, or abdominal. In addition, in rare
cases, a multiple gestation may be heterotopic (include both a uterine and extrauterine
pregnancy).
Ectopic pregnancy is a potentially life-threatening condition. While surgical approaches are the
mainstay of treatment, many women are candidates for medical therapy with methotrexate (MTX)
because of advances in early diagnosis [2]. The overall success rate of medical treatment in
properly selected women is nearly 90 percent [3,4].
Treatment of ectopic pregnancy with MTX will be reviewed here. The surgical treatment of ectopic
pregnancy is reviewed elsewhere (see "Ectopic pregnancy: Surgical treatment"). Related topics
regarding ectopic pregnancy are discussed in detail separately, including:
● Epidemiology, risk factors, and pathology (see "Ectopic pregnancy: Epidemiology, risk factors,
and anatomic sites")
● Clinical manifestations and diagnosis (see "Ectopic pregnancy: Clinical manifestations and
diagnosis")
● Choosing a treatment (see "Ectopic pregnancy: Choosing a treatment")
● Surgical management (see "Ectopic pregnancy: Surgical treatment")
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● Expectant management (see "Ectopic pregnancy: Expectant management")
● Diagnosis and management of uncommon sites of ectopic pregnancy (see "Abdominal

pregnancy, cesarean scar pregnancy, and heterotopic pregnancy")
INDICATIONS
Pharmacologic therapy is the preferred treatment for ectopic pregnancy, and MTX is the main
agent used. Some women require or choose surgical treatment. Only a small proportion of women
are candidates for expectant management (algorithm 1). (See "Ectopic pregnancy: Choosing a
treatment".)
The indication for pharmacologic management of ectopic pregnancy is a clinical diagnosis of

ectopic pregnancy in a woman who meets the selection criteria for MTX therapy and who prefers
pharmacologic management rather than surgical treatment.
The optimal candidates for a single-dose MTX treatment of ectopic pregnancy are women with the
following characteristics:
● Hemodynamically stable.
● No contraindications to MTX therapy.
● Serum beta-human chorionic gonadotropin (hCG) concentration ≤5000 mIU/mL.
● No fetal cardiac activity detected on transvaginal ultrasound.
● Willing and able to comply with post-treatment follow-up and with access to emergency
medical services within a reasonable timeframe in case of a ruptured fallopian tube.
Ectopic mass size less than 3 to 4 cm is also commonly used as a patient selection criterion;
however, this has not been confirmed as a predictor of successful treatment. Factors that impact
the efficacy of MTX are discussed in detail separately. (See "Ectopic pregnancy: Choosing a
treatment", section on 'Factors that impact efficacy'.)
CONTRAINDICATIONS
Some women are not appropriate candidates for MTX therapy and should be managed surgically,
including women with the following characteristics [5,6]:
● Intrauterine pregnancy
● Ruptured ectopic pregnancy

● Clinically important abnormalities in baseline hematologic, renal, or hepatic laboratory values.

MTX is renally cleared, and in women with renal insufficiency, a single dose of MTX can lead
to death or severe complications, including bone marrow suppression, acute respiratory
distress syndrome, and bowel ischemia. Dialysis does not provide normal renal clearance
[7,8]. Renal and liver disease may slow metabolism of MTX and result in pancytopenia and
skin and mucosal disorders [9]. MTX, especially with chronic administration such as for those
with psoriasis or rheumatoid arthritis, can be hepatotoxic. Similarly, it can cause suppression
of the bone marrow.
● Immunodeficiency, active pulmonary disease such as tuberculosis, or peptic ulcer disease.

The toxicity of MTX is enhanced in women with immune impairment. MTX may be associated
with pulmonary toxicity. In women with peptic ulcers, MTX may worsen the condition.
● Hypersensitivity to MTX
● Breastfeeding
Intermediate-dose MTX is used to treat ectopic pregnancy. Toxicities of high-dose MTX are
discussed in detail separately. (See "Therapeutic use and toxicity of high-dose methotrexate",
section on 'Overview of adverse effects'.)
CLINICAL PHARMACOLOGY
MTX is a folic acid antagonist widely used for treatment of neoplasia, severe psoriasis, and
rheumatoid arthritis. It inhibits DNA synthesis and cell reproduction, primarily in actively
proliferating cells such as malignant cells, trophoblasts, and fetal cells. MTX is rapidly cleared by
the kidneys, with 90 percent of an intravenous (IV) dose excreted unchanged within 24 hours of
administration [10].
Treatment of ectopic pregnancy uses an intermediate MTX dose (50 mg/m2 or 1 mg/kg). Low
doses (7.5 to 25 mg weekly) are typically used to treat rheumatologic disorders. High-dose MTX
(≥500 mg/m2) is used to treat some malignancies.
In some protocols, reduced folates (leucovorin, also called folinic acid, N5-formyl-tetrahydrofolate,
citrovorum factor) are given in combination with MTX to bypass the metabolic block induced by
MTX and thus rescue normal cells from toxicity. (See "Therapeutic use and toxicity of high-dose
methotrexate", section on 'Rationale for leucovorin rescue'.)
Route of administration — MTX can be given systemically (intravenously, intramuscularly, or

orally) or by direct local injection into the ectopic pregnancy sac transvaginally or laparoscopically.
Intramuscular administration is the most common route for treatment of tubal pregnancy [2].

Local injection is not generally used for tubal pregnancy, and has been found to be less effective
than salpingostomy [11]. Local treatment is highly operator dependent. Also, women bearing the
risks of laparoscopic surgery should have definitive treatment (ie, removal of the ectopic gestation
via salpingectomy or salpingostomy). Local injection is used in some cases of rare ectopic
gestation locations, such as cervical. (See "Cervical pregnancy", section on 'Treatment'.)
Adverse reactions — Adverse reactions to MTX are usually mild and self-limited. The most
common are stomatitis and conjunctivitis. Rare side effects include gastritis, enteritis, dermatitis,
pneumonitis, alopecia, elevated liver enzymes, and bone marrow suppression. Approximately 30
percent of patients in the single-dose protocol will have side effects; this rate is lower than with
multi-dose regimens (40 percent) [3]. (See "Major side effects of low-dose methotrexate".)
CLINICAL PROTOCOL
Pretreatment testing — Prior to treatment, a viable intrauterine pregnancy must be excluded.

Otherwise, a viable pregnancy might be exposed to harm from MTX administration [12].
A history and physical examination are performed. The history should include questions regarding
contraindications to MTX. (See 'Contraindications' above.)
The following laboratory and imaging tests are performed:
● Serum beta-human chorionic gonadotropin (hCG) – This is part of the diagnostic evaluation
and to establish a baseline to monitor the effect of therapy. (See "Ectopic pregnancy: Clinical
manifestations and diagnosis", section on 'Diagnostic evaluation'.)
● Transvaginal ultrasound – This is part of the diagnostic evaluation.
● Blood type and screen – This is to determine the need for anti-D immune globulin in women
who are Rh(D)-negative. (See "Prevention of Rh(D) alloimmunization in pregnancy".)
● Complete blood count and renal and liver function tests – This is to assess for
contraindications to MTX therapy. (See 'Contraindications' above.)
The diagnosis of ectopic pregnancy is discussed in detail separately. (See "Ectopic pregnancy:
Clinical manifestations and diagnosis".)
Efficacy of single versus multi-dose therapy — For women with tubal pregnancy treated with
MTX, we suggest a single-dose rather than a multiple-dose regimen.
We prefer an initial approach with single-dose therapy for tubal ectopic pregnancy for the following
reasons. The overall rate of resolution of ectopic pregnancy reported in the literature is
approximately 90 percent for both single- and multiple-dose protocols [3,11,13]. Multiple-dose
protocols appear to cause more adverse effects [3]. A single-dose approach is less expensive,
requires less intensive monitoring, and does not require leucovorin rescue. The following are
systematic reviews of the two regimens:
● A systematic review of two randomized trials compared single-dose with fixed multiple-dose
regimens [11]. There was no significant difference between treatment success rates, which
ranged from 89 to 91 percent for single-dose and from 86 to 93 percent for multi-dose therapy
[14,15]. There were no consistent findings regarding rates of complications between the two
dose regimens.
● Another systematic review included 26 observational studies of 1300 women with ectopic
pregnancy [3]. Overall success rates were lower for single- versus multiple-dose regimens, a
result that was statistically significant, but may not be clinically significant. This difference was
even larger after adjustment for factors such as hCG level and presence of embryonic cardiac
activity (odds ratio 4.74, 95% CI 1.77-12.62). However, significantly fewer side effects were
noted after single-dose versus multi-dose treatment (31 versus 41 percent).
In clinical use, protocols may overlap. Fourteen percent of patients on single-dose regimens
ultimately receive two or more doses, and 10 percent of patients on multi-dose regimens receive
just a single dose [3].
We reserve use of multi-dose MTX therapy to interstitial pregnancy or cervical pregnancy. (See
'Interstitial pregnancy' below and "Cervical pregnancy", section on 'Initial therapy: Methotrexate'.)
Single-dose protocol — The single-dose protocol is administration of a single IM dose of

MTX. Approximately 15 to 20 percent of women will require a second dose of MTX, and patients
should be made aware of this before starting the protocol [3,16]. Less than 1 percent of patients
need more than two doses [3].
In the single-dose protocol (table 1), Day 1 is the day that MTX is administered and an hCG
should also be measured [2,17]. The dose used is 50 mg per square meter of body surface area
(BSA) [18]. BSA may be calculated based upon height and weight on the day of treatment using
the formula BSA = square root ([cm X kg]/3600) or a BSA calculator (calculator 1). Protocols vary
slightly; choice of protocol depends on provider or institutional preference.
● In a commonly used protocol, on Days 4 and 7, a serum hCG concentration is drawn [5,6,19].
If the decrease in hCG between Days 4 and 7 is less than 15 percent, a second dose of MTX
50 mg/m2 IM is administered. It is common to observe an increase in hCG levels from day 1
through day 4, and this should not cause concern [20]. This is due to continued hCG
production by syncytiotrophoblast despite cessation of production by cytotrophoblast.
● If an additional dose of MTX is indicated, we do not repeat pretreatment laboratory testing

(complete blood count, renal and liver function tests); there are no data suggesting that one
dose of MTX changes the results of these tests.

Follow-up includes:
● After Day 7, hCG testing is repeated weekly. On Day 14:
• If there is a ≥15 percent hCG decline from Days 7 to 14, check hCG weekly until the level
is undetectable (this level varies by laboratory).
- If the hCG does not decline to zero, a new pregnancy should be excluded.
- In our practice, if three weekly values are similar, we give an additional dose of MTX
(50 mg/m2). This typically accelerates the decline of serum hCG.
• If there is a <15 percent hCG decline from Days 7 to 14, an additional dose of MTX 50
mg/m2 IM is given.
• If the hCG is rising, a transvaginal ultrasound should be performed.
We give a maximum of three doses of MTX. In rare cases in which the hCG falls <15 percent
between weekly measurements after a third dose, we perform a laparoscopic salpingostomy or
salpingectomy. (See "Ectopic pregnancy: Surgical treatment".)
Folinic acid rescue is not required for women treated with the single-dose protocol, even if a few
doses are ultimately given.
The hCG concentration usually declines to less than 15 mIU/mL by 35 days postinjection, but may
take as long as 109 days [16,21]. Alternatively, some patients have a slow clearance of serum
hCG. The risk of gestational trophoblastic disease is low.
There appears to be no clinical benefit from routine serial ultrasound examinations [22]. After
treatment, the ectopic pregnancy is often noted to increase in size and may persist for weeks on
serial ultrasound examinations. This probably represents hematoma rather than persistent
trophoblastic tissue and is not predictive of treatment failure. However, ultrasound evaluation for
peritoneal fluid is indicated for women with severe abdominal pain.
Multiple-dose protocol — The most common multiple-dose regimen is the administration of

MTX (1 mg/kg per day IM or intravenously [IV]) on Days 1, 3, 5, and 7, and intramuscular
leucovorin (0.1 mg/kg) on Days 2, 4, 6, and 8 [23]. hCG levels are drawn on Days 1, 3, 5, and 7. If
the serum hCG declines more than 15 percent from the previous measurement, treatment is
stopped and a surveillance phase begins.
The surveillance phase consists of weekly hCG measurements. If the hCG declines less than 15
percent from the previous level, the patient is given an additional dose of MTX 1 mg/kg IM
followed the next day with a dose of oral leucovorin 0.1 mg/kg. The hCG is followed until the level
is undetectable.

Precautions during therapy — Patients should adhere to the following precautions during MTX
treatment [6]:
● Avoid vaginal intercourse and new conception until hCG is undetectable.
● Avoid pelvic examinations during surveillance of MTX therapy due to theoretical risk of tubal
rupture.
● Avoid sun exposure to limit risk of MTX dermatitis.
● Avoid vitamins containing folic acid.
● It is common advice to avoid nonsteroidal anti-inflammatory drugs (NSAIDs), as the

interaction with MTX may decrease renal excretion of MTX and increase the risk of toxicity.
However, for rheumatologic disease, low-dose MTX is sometimes given concurrent with
NSAIDs with MTX with close monitoring; the dose given for ectopic pregnancy is considered
intermediate dose. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section
on 'Pharmacology' and "Therapeutic use and toxicity of high-dose methotrexate", section on
'Coadministered drugs that may interfere with excretion'.)
Pain after treatment — Mild to moderate abdominal pain of short duration (one to two days) at six
to seven days after receiving the MTX is common. The pain may be due to tubal abortion or tubal
distention from hematoma formation and can usually be controlled with acetaminophen.
A patient with severe pain should be further evaluated with transvaginal ultrasonography. Findings
suggestive of hemoperitoneum raise clinical suspicion of tubal rupture. In one study, three
parameters predicted hemoperitoneum ≥300 mL in women with ectopic pregnancy: moderate to
severe pelvic pain, fluid above the uterine fundus or around the ovary, and hemoglobin
concentration <10 g/dL [24]. A woman with none of these three criteria had a probability of 5.3
percent of hemoperitoneum ≥300 mL. When two or more criteria were present, the probability for
hemoperitoneum ≥300 mL reached 92.6 percent.
Women with severe pain should be closely observed for hemodynamic changes which may
accompany a tubal rupture. Falling hCG levels do not preclude the possibility of tubal rupture. If
tubal rupture is suspected, immediate surgery is required.
Severe pain alone in a hemodynamically stable patient is not an indication for surgery. As an
example, a review of 56 women with abdominal pain severe enough to be evaluated in the clinic
or emergency department, or requiring hospitalization, found that only eight patients subsequently
required surgery [25].
SUBSEQUENT PREGNANCY

Interval to conception — There has been no study addressing the earliest time to conceive after
MTX treatment of ectopic pregnancy. One study reported that patients with ectopic pregnancies
treated with MTX had a timely return of menses and superior rates of conception compared with
those treated with conservative surgical management [26]. However, a retrospective study of
controlled ovarian hyperstimulation after MTX treatment of ectopic pregnancy reported decreased
number of oocytes in the cycle within 180 days after MTX compared with that in later days [27].
The safe interval from MTX treatment to conception is unclear. Toxicology literature recommends
a four- to six-month washout period before attempting to become pregnant [28,29]. A retrospective
study of women who conceive after MTX treatment for ectopic pregnancy found no difference in
fetal malformation and adverse outcome rates in those who conceived within less than six months
compared with six or more months [30]. Thus, since there is no apparent deleterious effect of
previous MTX treatment on the offspring, it is reasonable to allow the patients to conceive.
However, residual MTX may be stored in the liver and kidney for months.
We advise women not to conceive for three months [6]. On the other hand, there is no evidence of
teratogenic risk to those who conceive sooner. Women trying to conceive should take the folate
daily, according to routine preconception recommendations. (See "Folic acid supplementation in
pregnancy".)
Obstetric outcome — There is no evidence of adverse effects of MTX treatment of ectopic

pregnancy on future pregnancies [31-34].
INTERSTITIAL PREGNANCY
We treat interstitial pregnancy (located at the junction of the fallopian tube and uterine cavity)
initially with multi-dose MTX (figure 1 and table 1) [23,35-38], resorting to surgical therapy if there
is any deterioration in clinical status. (See 'Multiple-dose protocol' above.)
There are no high-quality data comparing single-dose versus multi-dose MTX therapy for
interstitial pregnancy. A few authors have advocated treatment of interstitial pregnancy by local
MTX or potassium chloride (KCl) injection into the ectopic gestation. The dose of MTX is 1 mg/kg
body weight, a single dose of 100 mg or 50 mg/m2 body surface. The reported success rate is
approximately 90 percent [39,40]. In the presence of fetal cardiac activity or in heterotopic
pregnancy, local injection of KCl 20% is preferred [38]. There are also case reports of
management of interstitial pregnancy using selective arterial embolization alone or with MTX
[41,42].
With multi-dose MTX for interstitial pregnancy, success rates of 66 to 100 percent have been
reported [37]. In one study, the mean duration to achieve an undetectable serum human chorionic
gonadotropin (hCG) concentration was 43±64 days [36].

A residual interstitial mass or heterogeneous area with persistent vascularity on ultrasound has
been reported despite complete hCG resolution [43,44]. Close follow-up in patients treated
medically is advised. In those with increasing abdominal pain, early surgical intervention should be
considered. After medical treatment of an interstitial pregnancy, there is an unknown risk of uterine
rupture in a future pregnancy [45].
Surgical treatment of interstitial pregnancy is discussed separately. (See "Ectopic pregnancy:

Surgical treatment", section on 'Interstitial pregnancy'.)
NONTUBAL ECTOPIC PREGNANCY
Medical and surgical management of heterotopic, cervical, cesarean scar, or abdominal

pregnancy are discussed separately. (See "Cervical pregnancy" and "Abdominal pregnancy,
cesarean scar pregnancy, and heterotopic pregnancy".)
COMBINED USE WITH OTHER MEDICATIONS
Combined use of MTX with other medications has been studied. However, combination therapy is
not commonly used since it adds cost and potential complications, while MTX alone is an effective
therapy.
Mifepristone — Treatment of ectopic pregnancy using a combination of mifepristone and MTX

has been investigated [11]. A systematic review that included two randomized trials that compared
single-dose MTX (50 mg/m2) alone with intramuscular MTX in combination with oral mifepristone
(600 mg) found a statistically lower success rate for MTX alone (61 versus 72 percent; odds ratio
0.59, 95% CI 0.35-0.99), but the trials were small (n = 124 and 138). No differences were found in
tubal preservation or tubal patency. No data are available on future fertility. More studies are
needed to fully evaluate whether the addition of mifepristone to MTX regimens is beneficial.
We do not use mifepristone in combination with MTX for treatment of ectopic pregnancy.
Other agents — Preliminary research has been done to investigate use of a combination of MTX
and gefitinib, a medication used in the treatment of non-small cell lung cancer and breast cancer
[46,47]. Gefitinib selectively inhibits the tyrosine kinase domain of epidermal growth factor receptor
and the placenta has the highest expression of epidermal growth factor of all nonmalignant
tissues. In a small case series of 12 women with an ectopic pregnancy, combination therapy with
MTX plus gefitinib resulted in a faster decline of serum human chorionic gonadotropin, a marker of
trophoblastic activity, than treatment of historical controls with MTX alone [47]. Gefitinib may result
in interstitial lung disease, particularly in patients of Japanese ancestry. Further study is needed
before gefitinib can be used to treat ectopic pregnancy.

SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Ectopic pregnancy".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Ectopic pregnancy (The Basics)")
● Beyond the Basics topics (see "Patient education: Ectopic (tubal) pregnancy (Beyond the
Basics)")
SUMMARY AND RECOMMENDATIONS
● An ectopic pregnancy is an extrauterine pregnancy. Almost all ectopic pregnancies occur in

the fallopian tube (96 percent). (See 'Introduction' above.)
● For women with tubal pregnancy treated with methotrexate (MTX), we suggest a single-dose
over multiple-dose regimen (Grade 2B). However, we use a multi-dose regimen for interstitial
pregnancy. (See 'Efficacy of single versus multi-dose therapy' above.)
● The ideal candidates for MTX treatment are women with ectopic pregnancy who meet the
following criteria (see 'Indications' above):
• Hemodynamically stable.
• Have no renal, hepatic, or hematologic disorders.
• Able and willing to comply with post-treatment monitoring.
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• Pretreatment serum beta-human chorionic gonadotropin (hCG) concentration less than

5000 mIU/mL.
• Tubal size of less than 3 to 4 cm and no fetal cardiac activity (these are not independent
predictors of MTX treatment success).
● Pretreatment testing includes serum hCG, complete blood count, and renal and liver function
tests. (See 'Pretreatment testing' above.)
● In single-dose protocols, intramuscular MTX is given followed by an hCG level on treatment

Day 4 and 7 and then weekly. If the decrease in hCG between Days 4 and 7 is less than 15
percent, a second dose of MTX 50 mg/m2 intramuscularly is administered. Additional doses
of MTX are given if the hCG does not decline sufficiently. The hCG is followed until the level is
undetectable. (See 'Single-dose protocol' above.)
● In multiple-dose protocols, MTX is given on Days 1, 3, 5, and 7 and leucovorin on Days 2, 4,

6, and 8. If the serum hCG concentration plateaus or increases in two consecutive
measurements, a second course may be given seven days after the previous dose. HCG is
followed weekly until undetectable. (See 'Multiple-dose protocol' above.)
● Mild abdominal pain of short duration (one to two days) that occurs six to seven days after
receiving the medication is common. Women with severe pain should be observed closely for
hemodynamic changes which may accompany a tubal rupture. Clinical suspicion of a tubal
rupture is an indication for immediate surgery. (See 'Pain after treatment' above.)
● We treat interstitial pregnancy (located at the junction of the fallopian tube and uterine cavity)
initially with multi-dose MTX, although some clinicians use local injection of MTX. (See
'Interstitial pregnancy' above.)
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34. Kung FT, Chang SY, Tsai YC, et al. Subsequent reproduction and obstetric outcome after
methotrexate treatment of cervical pregnancy: a review of original literature and international
collaborative follow-up. Hum Reprod 1997; 12:591.
35. Tulandi T, Al-Jaroudi D. Interstitial pregnancy: results generated from the Society of
Reproductive Surgeons Registry. Obstet Gynecol 2004; 103:47.
36. Lau S, Tulandi T. Conservative medical and surgical management of interstitial ectopic
pregnancy. Fertil Steril 1999; 72:207.
37. Jermy K, Thomas J, Doo A, Bourne T. The conservative management of interstitial

pregnancy. BJOG 2004; 111:1283.
38. Moawad NS, Mahajan ST, Moniz MH, et al. Current diagnosis and treatment of interstitial
pregnancy. Am J Obstet Gynecol 2010; 202:15.
39. Timor-Tritsch IE, Monteagudo A, Lerner JP. A 'potentially safer' route for puncture and
injection of cornual ectopic pregnancies. Ultrasound Obstet Gynecol 1996; 7:353.
40. Monteagudo A, Minior VK, Stephenson C, et al. Non-surgical management of live ectopic
pregnancy with ultrasound-guided local injection: a case series. Ultrasound Obstet Gynecol
2005; 25:282.
41. Deruelle P, Lucot JP, Lions C, Robert Y. Management of interstitial pregnancy using selective
uterine artery embolization. Obstet Gynecol 2005; 106:1165.
42. Ophir E, Singer-Jordan J, Oettinger M, et al. Uterine artery embolization for management of
interstitial twin ectopic pregnancy: case report. Hum Reprod 2004; 19:1774.
43. Verity L, Ludlow J, Dickinson JE. Interstitial ectopic pregnancy: a contemporary case series.
Aust N Z J Obstet Gynaecol 2003; 43:232.
44. Tang A, Baartz D, Khoo SK. A medical management of interstitial ectopic pregnancy: a 5-
year clinical study. Aust N Z J Obstet Gynaecol 2006; 46:107.
45. Downey GP, Tuck SM. Spontaneous uterine rupture during subsequent pregnancy following
non-excision of an interstitial ectopic gestation. Br J Obstet Gynaecol 1994; 101:162.

46. Nilsson UW, Johns TG, Wilmann T, et al. Effects of gefitinib, an epidermal growth factor
receptor inhibitor, on human placental cell growth. Obstet Gynecol 2013; 122:737.
47. Skubisz MM, Horne AW, Johns TG, et al. Combination gefitinib and methotrexate compared
with methotrexate alone to treat ectopic pregnancy. Obstet Gynecol 2013; 122:745.
Topic 5407 Version 30.0

GRAPHICS
Algorithm: Choosing a treatment for ectopic pregnancy
hCG: human chorionic gonadotropin; TVUS: transvaginal ultrasound; MTX: methotrexate.

* Severe or persistent lower abdominal pain and/or evidence of hematoperitoneum.
¶ Serum quantitative beta-hCG.
Δ Some clinicians treat with MTX for patients with hCG >5000 to ≤10,000 mIU/mL if the
following criteria are met: no free fluid in the pelvic cul-de-sac or abdomen, pelvic ultrasound
meets criteria for methotrexate, and the patient has minimal pelvic or abdominal pain.
◊ Ectopic mass diameter <3 to 4 cm is also commonly used as a patient selection criterion;
however, this has not been confirmed as a predictor of successful treatment.
Graphic 114571 Version 3.0

Methotrexate treatment protocol for tubal or interstitial ectopic pregnancy
Pretreatment testing and instructions

hCG concentration
Transvaginal ultrasound
Blood group and Rh(D) typing; give anti Rh(D) immune globulin (Rho[D] immune globulin) 300 mcg IM, if
indicated
Complete blood count
Liver and renal function tests
Discontinue folic acid supplements
Counsel patient to avoid nonsteroidal anti-inflammatory medications, recommend acetaminophen if an analgesic

is needed
Advise patient to refrain from sexual intercourse and strenuous exercise
Treatment
Single-dose protocol Multiple-dose protocol
day
1 hCG concentration hCG concentration
Methotrexate 50 mg/m 2 BSA IM Methotrexate 1 mg/kg body weight IM or IV

A calculator useful for determining BSA from
patient height and body weight is available
separately in UpToDate
2 Leucovorin 0.1 mg/kg orally
3 hCG
If <15 percent hCG decline from Day 1 to 3,

give methotrexate 1 mg/kg IM or IV
If ≥15 percent decline from Day 1 to 3, begin

weekly hCG
4 hCG Leucovorin 0.1 mg/kg orally*
5 hCG
If <15 percent decline from Day 3 to 5

methotrexate, give methotrexate 1 mg/kg IM or IV
If ≥15 percent decline from day 3 to 5, begin

weekly hCG
6 Leucovorin 0.1 mg/kg orally*
7 hCG hCG
If <15 percent hCG decline from Day 4 to 7, If <15 percent decline from Day 5 to 7
give additional dose of methotrexate 50 methotrexate, give methotrexate 1 mg/kg IM or IV
mg/m 2 IM
If ≥15 percent hCG decline from Day 4 to 7, If ≥15 percent decline from Day 5 to 7, begin
draw hCG concentration weekly until hCG is weekly hCG
undetectable
8 Leucovorin 0.1 mg/kg orally*
14 hCG hCG
If <15 percent hCG decline from Day 7 to If <15 percent hCG decline from Day 7 to 14, give
14, give additional dose of methotrexate 50 additional dose of methotrexate 1 mg/kg IM
mg/m 2 IM (give leucovorin 0.1 mg/kg orally on Day 15)
If ≥15 percent hCG decline from Day 7 to If ≥15 percent hCG decline from Day 7 to 14,
14, check hCG weekly until undetectable check hCG weekly until undetectable
21 and 28 If three doses have been given and there is a If five doses have been given and there is a <15
<15 percent hCG decline from Day 21 to 28, percent hCG decline from Day 14 to 21, proceed
proceed with laparoscopic surgery with laparoscopic surgery

Laparoscopy
If severe abdominal pain or an acute abdomen suggestive of tubal rupture occurs
If ultrasonography reveals greater than 300 mL pelvic or other intraperitoneal fluid
hCG: human chorionic gonadotropin beta-subunit; BSA: body surface area; IV: intravenously; IM: intramuscularly.
* Leucovorin is given only if methotrexate was given on the previous day. Leucovorin may also be administered IM.
Data from:
1. Barnhart KT. Clinical practice. Ectopic pregnancy. N Engl J Med 2009; 361:379.
2. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 94: Medical management of
ectopic pregnancy. Obstet Gynecol 2008; 111:1479.

Normal female reproductive anatomy

Contributor Disclosures
Togas Tulandi, MD, MHCM Consultant/Advisory Boards: AbbVie [Gonadotropin-releasing hormone
antagonist (Elagolix)]. Courtney A Schreiber, MD, MPH Grant/Research/Clinical Trial Support: Bayer
[Contraception (IUD)]; Medicines360 [Contraception (IUD)]; VeraCept [Contraception (IUD)]. Patent holder:
Penn, Saul [Medical management of nonviable pregnancy]. Sandy J Falk, MD, FACOG Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy

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Official reprint from UpToDate®

Ectopic pregnancy: Methotrexate therapy

● Choosing a treatment (see "Ectopic pregnancy: Choosing a treatment")

● Surgical management (see "Ectopic pregnancy: Surgical treatment")

https://www.uptodate.com/contents/ectopic-pregnancy-methotrexate-therapy/print?search=metotrexato para el embarazo ectópico&source=sear… 1/20

● Expectant management (see "Ectopic pregnancy: Expectant management")

● Diagnosis and management of uncommon sites of ectopic pregnancy (see "Abdominal

The indication for pharmacologic management of ectopic pregnancy is a clinical diagnosis of

● No contraindications to MTX therapy.

● Serum beta-human chorionic gonadotropin (hCG) concentration ≤5000 mIU/mL.

● No fetal cardiac activity detected on transvaginal ultrasound.

● Ruptured ectopic pregnancy

https://www.uptodate.com/contents/ectopic-pregnancy-methotrexate-therapy/print?search=metotrexato para el embarazo ectópico&source=sear… 2/20

● Clinically important abnormalities in baseline hematologic, renal, or hepatic laboratory values.

● Immunodeficiency, active pulmonary disease such as tuberculosis, or peptic ulcer disease.

Route of administration — MTX can be given systemically (intravenously, intramuscularly, or

https://www.uptodate.com/contents/ectopic-pregnancy-methotrexate-therapy/print?search=metotrexato para el embarazo ectópico&source=sear… 3/20

Pretreatment testing — Prior to treatment, a viable intrauterine pregnancy must be excluded.

The following laboratory and imaging tests are performed:

● Transvaginal ultrasound – This is part of the diagnostic evaluation.

Single-dose protocol — The single-dose protocol is administration of a single IM dose of

● If an additional dose of MTX is indicated, we do not repeat pretreatment laboratory testing

https://www.uptodate.com/contents/ectopic-pregnancy-methotrexate-therapy/print?search=metotrexato para el embarazo ectópico&source=sear… 5/20

● After Day 7, hCG testing is repeated weekly. On Day 14:

• If the hCG is rising, a transvaginal ultrasound should be performed.

Multiple-dose protocol — The most common multiple-dose regimen is the administration of

https://www.uptodate.com/contents/ectopic-pregnancy-methotrexate-therapy/print?search=metotrexato para el embarazo ectópico&source=sear… 6/20

● Avoid vaginal intercourse and new conception until hCG is undetectable.

● Avoid sun exposure to limit risk of MTX dermatitis.

● Avoid vitamins containing folic acid.

● It is common advice to avoid nonsteroidal anti-inflammatory drugs (NSAIDs), as the

https://www.uptodate.com/contents/ectopic-pregnancy-methotrexate-therapy/print?search=metotrexato para el embarazo ectópico&source=sear… 7/20

Obstetric outcome — There is no evidence of adverse effects of MTX treatment of ectopic

https://www.uptodate.com/contents/ectopic-pregnancy-methotrexate-therapy/print?search=metotrexato para el embarazo ectópico&source=sear… 8/20

Surgical treatment of interstitial pregnancy is discussed separately. (See "Ectopic pregnancy:

NONTUBAL ECTOPIC PREGNANCY

Medical and surgical management of heterotopic, cervical, cesarean scar, or abdominal

COMBINED USE WITH OTHER MEDICATIONS

Mifepristone — Treatment of ectopic pregnancy using a combination of mifepristone and MTX

https://www.uptodate.com/contents/ectopic-pregnancy-methotrexate-therapy/print?search=metotrexato para el embarazo ectópico&source=sear… 9/20

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topics (see "Patient education: Ectopic pregnancy (The Basics)")

SUMMARY AND RECOMMENDATIONS

● An ectopic pregnancy is an extrauterine pregnancy. Almost all ectopic pregnancies occur in

• Have no renal, hepatic, or hematologic disorders.

• Able and willing to comply with post-treatment monitoring.

https://www.uptodate.com/contents/ectopic-pregnancy-methotrexate-therapy/print?search=metotrexato para el embarazo ectópico&source=se… 10/20

• Pretreatment serum beta-human chorionic gonadotropin (hCG) concentration less than

● In single-dose protocols, intramuscular MTX is given followed by an hCG level on treatment

● In multiple-dose protocols, MTX is given on Days 1, 3, 5, and 7 and leucovorin on Days 2, 4,

Use of UpToDate is subject to the Subscription and License Agreement.

1. Bouyer J, Coste J, Fernandez H, et al. Sites of ectopic pregnancy: a 10 year population-

3. Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic

https://www.uptodate.com/contents/ectopic-pregnancy-methotrexate-therapy/print?search=metotrexato para el embarazo ectópico&source=sea… 11/20

4. Morlock RJ, Lafata JE, Eisenstein D. Cost-effectiveness of single-dose methotrexate

6. Practice Committee of American Society for Reproductive Medicine. Medical treatment of

9. Willner N, Storch S, Tadmor T, Schiff E. Almost a tragedy: severe methotrexate toxicity in a

https://www.uptodate.com/contents/ectopic-pregnancy-methotrexate-therapy/print?search=metotrexato para el embarazo ectópico&source=se… 12/20

24. Fauconnier A, Mabrouk A, Salomon LJ, et al. Ultrasound assessment of haemoperitoneum

37. Jermy K, Thomas J, Doo A, Bourne T. The conservative management of interstitial

https://www.uptodate.com/contents/ectopic-pregnancy-methotrexate-therapy/print?search=metotrexato para el embarazo ectópico&source=se… 14/20