Accepted Manuscript

Pregnancy of Unknown Location: Evaluation and Management

Daniela Carusi MD, MSc

PII: S0146-0005(18)30142-3
DOI: https://doi.org/10.1053/j.semperi.2018.12.006
Reference: YSPER 51107

To appear in: Seminars in Perinatology

Please cite this article as: Daniela Carusi MD, MSc , Pregnancy of Unknown Location: Evaluation and
Management, Seminars in Perinatology (2018), doi: https://doi.org/10.1053/j.semperi.2018.12.006

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service
to our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and
all legal disclaimers that apply to the journal pertain.
 ACCEPTED MANUSCRIPT

Pregnancy of Unknown Location: Evaluation and Management

Daniela Carusi, MD, MSc*
Brigham & Women’s Hospital and Harvard Medical School, Boston, MA

*
Corresponding author at: Department of Obstetrics & Gynecology, Brigham & Women’s

T
Hospital, 75 Francis St., Boston, MA 02115, dcarusi@bwh.harvard.edu, 617-732-5452, 617-232-

IP
6346 (fax)

CR
Abstract

US
Early diagnosis of an extrauterine pregnancy is important for safe and effective management.

However, a pregnancy’s location often cannot be easily determined with abnormal implantations
AN
or prior to 5-6 weeks’ gestation. Multiple testing strategies exist to diagnose an abnormal

pregnancy when location is unknown, but caution needs to be used to avoid a false diagnosis.
M

Medical treatment is optimal when an abnormal pregnancy is diagnosed early. Because most of

these pregnancies are intrauterine, additional testing to localize the pregnancy will allow the
ED

correct choice of therapy and avoids unnecessary exposure to a toxic therapy. This testing
PT

strategy should be reserved for patients with significant concern for ectopic pregnancy, based on

either risk factors or clinical findings. Overuse of this approach can lead to interruption of
CE

normal pregnancies.
AC
 ACCEPTED MANUSCRIPT

The term “Pregnancy of Unknown Location,” or PUL can apply to any pregnancy in the first five

weeks following a woman’s last menstrual period, or three weeks following conception. During

this time an embryo will have implanted but is too small to be seen on imaging. While 98% of

pregnancies will be normally implanted in the uterine cavity, abnormal or ectopic implantations

can occur in the fallopian tubes, cervix, uterine cornua, within a cesarean section scar, or, even

T
more rarely, in the ovaries, pelvis or abdomen.1 Ectopic implantations are at risk for organ

IP
rupture and massive bleeding, so early diagnosis is critical to their safe management. When this

CR
diagnosis is suspected for any reason, close follow-up and a systematic approach to diagnosis

can hasten pregnancy localization and minimize maternal morbidity.

US
AN
M

Confirming Pregnancy Location

There are two means of knowing a pregnancy’s location: Visual and histologic. Both methods
ED

have limitations, given that radiologic confirmation cannot happen before 5-6 weeks’ gestation,

and histologic confirmation often requires disruption of the pregnancy. This may leave an
PT

interval of one to two weeks between confirmation that a woman is pregnant and affirming that it
CE

is in the proper location.

Visual Confirmation
AC

Transvaginal ultrasound (TVUS) is the radiologic method of choice for visualizing a pregnancy.

The first sign of an intrauterine pregnancy (IUP) is a small sac located eccentrically within the

decidua. This then evolves into a “double decidual” sign, with two rings of tissue around the sac.

While an intradecidual sac may be apparent prior to five weeks’ gestation, its sensitivity and
 ACCEPTED MANUSCRIPT

specificity may be too low to confirm an IUP.2 During the fifth week the double decidual sign

will become visible on abdominal ultrasound, while a yolk sac will become visible on TVUS.

Subsequently, an embryonic pole will appear at approximately six weeks. These findings are

much more specific for IUP but should be confirmed by an experienced sonologist. An IUP can

be absolutely confirmed by the presence of an intrauterine sac with an embryo that has a

T
detectable heartbeat; however, the earliest that this can occur is the sixth week of pregnancy with

IP
transvaginal ultrasound (TVUS).

CR
It is important to consider the quality of the ultrasound when interpreting the images.3 Patients

US
with significant uterine fibroids or high body mass index may have more limited imaging, which

should be considered when an IUP cannot be seen. In such situations IUP confirmation may need
AN
to take place at an even later gestational age. MRI has been used to identify a pregnancy’s

location in extreme situations, such as with large obstructing fibroids. However, the sensitivity
M

and specificity of specific MRI features have not been well studied.4 Furthermore, the potential

risks of gadolinium contrast exposure need to be weighed against the importance of improved
ED

diagnosis on a case-by-case basis.5

PT

When imaging cannot confirm an IUP, it may be able to confirm an ectopic implantation in the

eyes of an experienced examiner. Because treatment of the ectopic pregnancy often involves
CE

pregnancy-harming procedures (medical or surgical), it is important to have high diagnostic

AC

confidence prior to intervention. As with IUP confirmation, the best diagnostic confirmation

comes with detection of a fetal heartbeat (FH) outside of the endometrial cavity, though an FH

does not develop in all ectopic gestations. Other signs include a gestational sac with or without a

yolk sac in an ectopic location, or a complex adnexal mass that appears inconsistent with a

hemorrhagic corpus luteum. While these findings may be seen earlier than an FH, their accuracy
 ACCEPTED MANUSCRIPT

depends on the experience of the sonologist, and they are necessarily less specific than a fetal

pole or heartbeat for diagnosing ectopic pregnancy.

When location cannot be confirmed with high enough radiologic certainty, direct visualization

may be an option. This is usually accomplished with a diagnostic laparoscopy, with visualization

T
of a suspicious mass in the pelvis. As with radiologic confirmation, this requires experience on

IP
the part of the surgeon, and may be limited by the presence of pelvic adhesions or otherwise

CR
abnormal anatomy. Very early and small ectopic gestations may be missed with this method, as

well as cervical or cesarean scar implantations. Surgical confirmation is generally employed

US
when there is very high suspicion for ectopic implantation, or when immediate diagnosis is

necessary at an early gestation. The method carries the advantage of simultaneous treatment
AN
when the location is confirmed, though drawbacks include the inherent risks of surgery and

general anesthesia.
M

Histologic Confirmation
ED

Histologic confirmation involves removing tissue from a specific location and confirming the

presence of trophoblast or chorionic villi. This approach is most often used to confirm an
PT

intrauterine implantation by sending endometrial curettings or spontaneously passed tissue to a

CE

pathologist. Ectopic location is confirmed when placental tissue is identified from an extrauterine

source. Absence of trophoblastic or villi in an endometrial sample does not necessarily confirm
AC

ectopic location, as 15-40% of early or failed intrauterine pregnancies can be missed with

histologic analysis.6, 7

Patient and Test Selection

 ACCEPTED MANUSCRIPT

Short of visualizing a fetal heartbeat radiologically or an ectopic mass surgically, none of the

tests described here has perfect diagnostic accuracy. Interpretation of these diagnostic tests

involves a tradeoff between falsely calling a normal IUP abnormal, leading to its interruption, or

missing an ectopic pregnancy diagnosis, leading to maternal harm or a foregone opportunity for

medical management. Selecting appropriate tests and setting a threshold for calling a pregnancy

T
abnormal involves individualized patient assessment and counseling.

IP
CR
At one extreme, patients who verify that the pregnancy is undesired can be assessed as

candidates for pregnancy interruption. With appropriate termination counseling and consent, the

US
uterus can be evacuated, and the tissue examined to confirm IUP. At the opposite extreme,

patients may set a very high personal threshold for labeling a pregnancy abnormal. This may be
AN
especially true for patients with an infertility history. These patients should be carefully

counseled about the risk of inaccurate diagnosis, which may involve discussion with the
M

radiologists about diagnostic certainty of a suspected ectopic gestation or absence of IUP

confirmation. For these patients, confirmation of multiple abnormal test findings will produce
ED

more certainty than reliance on a single study.8

PT

As with any assay, the positive predictive value for a test of abnormal or ectopic pregnancy

depends on the pretest probability of the diagnosis. Importantly, these tests generally have not
CE

been studied in women with no risk factors for or symptoms of an abnormal pregnancy. Such
AC

women are more likely to experience a false positive result if subjected to the above testing. This

is evidenced in studies of the -hCG Discriminatory Zone: Studies showing a lower (1500

mIU/mL) cutoff looked at women with concern for ectopic pregnancy, while those showing

failed visualization of a normal IUP at higher -hCG cutoffs included any patients undergoing

simultaneous laboratory testing and ultrasound.9, 10 For this reason, this testing algorithm should
 ACCEPTED MANUSCRIPT

be reserved for women at increased concern for ectopic implantation. Significant risk factors for

and clinical signs of abnormal pregnancy are listed in Table 1.

Finally, any patient who has clinical concern for active bleeding or pregnancy rupture –

including hemodynamic instability, orthostasis, peritoneal signs on exam, or a hemoperitoneum

on imaging – should go directly to surgical confirmation and treatment. This also applies to

T
IP
patients who cannot comply with close follow-up or cannot access emergency care. Such patients

CR
should either complete their diagnostic workup as inpatients or undergo surgical diagnosis and

treatment, with the decision based on the level of concern for ectopic pregnancy.

Diagnostic Workup
US
AN
Three possibilities exist when an IUP is not seen by ultrasound: (1) The pregnancy is ectopic, (2)

The pregnancy is intrauterine but too early for ultrasound detection, or (3) The pregnancy is
M

intrauterine but abnormal. Any intrauterine pregnancy may be left alone, and viability can be

later confirmed without significant maternal morbidity. However, if the pregnancy is ectopic,
ED

delays in diagnosis can lead to major hemorrhage and/or diminished fertility. Therefore, location

may need to be confirmed before an IUP can be practically visualized. Because this often
PT

involves either evacuation of uterine contents or empiric treatment with toxic medications, it is
CE

critical to confirm that the pregnancy is abnormal (either ectopic or abnormal IUP) before

intervening further with a desired pregnancy. One or, preferably, multiple tests can be used to
AC

confirm pregnancy abnormality prior to an invasive diagnostic or therapeutic intervention.

Failed visualization with confirmed pregnancy dating

As described above, an intrauterine pregnancy should be seen by transvaginal ultrasound by six

weeks’ gestational age. Thus, the absence of a visualized gestational sac by this time is
 ACCEPTED MANUSCRIPT

concerning for ectopic location. In addition to limits of image quality and provider experience,

using this criterion requires confirmed pregnancy dating. This is best accomplished with

laboratory confirmation of ovulation timing or known date of embryo transfer. While last

menstrual period dating is generally reliable for women with regular menstrual cycles, variation

can occur, and this should not be relied upon for ectopic pregnancy confirmation. With the

T
availability of quantitative serum β-hCG testing, reliance on known conception timing for non-

IP
IVF patients has become nearly obsolete.

CR
Failed visualization plus quantitative -hCG

US
Due to limitations in pregnancy dating, quantitative levels of serum β-hCG can be used to

estimate gestational age prior to pregnancy visualization. The level of -hCG at which a viable
AN
IUP should be seen radiologically is known as the Discriminatory Zone (DZ); absence of a

visualized IUP at a -hCG level above this level is suspicious for ectopic location or nonviable
M

IUP.
ED

Based on a review of -hCG levels with known pregnancy locations, a level of 1500 IU/ml has

been proposed as the appropriate DZ with TVUS.9 A higher level (6500-7000) needs to be used
PT

with transabdominal imaging. The authors of this original publication recommended that each
CE

center should determine a DZ using its own radiologists and laboratory; however, this is not

practical for most centers. While many institutions use the published DZ of 1500-2000 to
AC

diagnose abnormal implantation, cautionary publications have documented viable IUPs that were

not seen by ultrasound with -hCG levels as high as 4000 IU/ml.10, 11 Thus, caution should be

used when using this tool in isolation with desired pregnancies.

Serial -hCG levels

 ACCEPTED MANUSCRIPT

The above diagnostic tools have the advantage of completion in a single patient encounter – an

important consideration with a time-sensitive diagnosis. However, additional data is needed

when dating is uncertain or the -hCG level is below an acceptable discriminatory zone.

Following serial -hCG levels is a commonly used method in these settings.

T
With this method, -hCG levels are drawn 48 hours apart, and the level should roughly double if

IP
the pregnancy is normal. As with any other test, patient and laboratory variation can produce

CR
imperfect results, and lesser degrees of rise can be seen with normal IUPs. The predictive value

of -hCG rise has been studied: a rise of < 67% predicts abnormal pregnancy with 95%

US
certainty, while a rise of <53% gives 99% certainty.8, 12 Because misdiagnosis and interruption of

a normal pregnancy is unacceptable to most patients, the lower cutoff is generally used. For
AN
some patients, even this 1% possibility of incorrect diagnosis is not acceptable; in this case, a rise

of 35% or less can be used to obtain a 99.9% level of certainty.12 However, using the lower
M

cutoffs necessarily risks delayed or missed diagnosis of an ectopic pregnancy. These

ED

considerations should be discussed carefully with individual patients in determining a course of

action.
PT

Serum progesterone level

CE

The absolute level of serum progesterone has been used as an additional test to diagnose an

abnormal pregnancy. A metanalysis of cohort studies showed that for women with symptoms of
AC

abnormal pregnancy and an indeterminate ultrasound, a very low progesterone level (3-6 ng/ml)

indicated an abnormal gestation with 99% certainty.13 As with the other tests, this single reading

will not always be accurate, and will not be useful if the patient is using exogenous sources of

progesterone.
 ACCEPTED MANUSCRIPT

Intervention

Once the provider and patient feel convinced that a pregnancy is abnormal, either medical or

surgical treatment options are available. The specific treatments will vary based on an

intrauterine or ectopic location. Medical treatment of an abnormal intrauterine pregnancy

T
involves a drug (misoprostol) that will allow expulsion of the trophoblast, with or without the

IP
addition of a drug to interrupt implantation (mifepristone).14 Alternatively, medical treatment of

CR
an ectopic pregnancy involves a direct cytotoxic agent, systemic methotrexate, or directly

injected methotrexate or potassium chloride. Surgical treatment of an intrauterine pregnancy

US
requires uterine evacuation; alternatively, surgical ectopic pregnancy treatment is accomplished

via pelviscopy or occasionally laparotomy.

AN
Some controversy exists as to whether an ectopic location should be confirmed before treating an

abnormal pregnancy. Without ultrasound confirmation of ectopic pregnancy, localization will

M

require surgical evacuation of the uterus, which may risk patient discomfort and, rarely,
ED

endometrial or uterine damage. In avoiding this step, giving empiric systemic methotrexate is

expected to interrupt the pregnancy in any location, with a small intrauterine pregnancy passing
PT

when withdrawal bleeding ensues.

CE

Alternatively, some argue against empiric ectopic pregnancy treatment because most abnormal

pregnancies are intrauterine.15 Based on this argument, uterine evacuation will fill both a
AC

diagnostic and often therapeutic role. Follow-up -hCG laboratory testing can help to confirm

that a pregnancy was interrupted with uterine evaluation: A fall of 15-20% in 12-24 hours

strongly suggests pregnancy interruption, and the levels can then be serially followed until

undetectable.16 Additional arguments against empiric treatment include appropriate expectations

and follow-up with future pregnancy, as patients who are labeled as having a prior ectopic
 ACCEPTED MANUSCRIPT

pregnancy will be followed differently than those with a prior failed IUP. From an academic

perspective, erroneously labeling failed intrauterine pregnancies as ectopic leads to

overestimations of medical therapy’s success rate.17

Once an ectopic implantation is confirmed, medical or surgical treatment may be selected.

T
Beyond the requirement of hemodynamic stability, this choice is driven by two main factors: the

IP
absolute level of -hCG, and the patient’s ability to undergo treatment with a chemotherapeutic

CR
agent and comply with weeks of follow-up. Medical therapy usually involves systemic

administration of methotrexate, a folinic acid inhibitor that blocks cell division. Prior to this

US
treatment, renal, liver, pulmonary, and peptic ulcer disease must be excluded, and the visualized

adnexal mass, if seen, should be less than 4 cm. Medical management is generally offered when
AN
the serum -hCG level is less than 5000 IU/ml, and has a success rate greater than 90% in this

setting.18 Success rates fall and rupture rates increase with higher hCG levels. When a patient has
M

medical contraindications to methotrexate or a high hCG level, but surgery is undesirable, direct

injection of the pregnancy with potassium chloride has been successful.19 This treatment may be
ED

combined with systemic methotrexate with particularly challenging pregnancies. This requires an
PT

experienced operator with ultrasound guided injections/ aspirations.

The protocols for Methotrexate therapy are shown in Table 2. The regimen names refer to the
CE

intended number of doses, “Single,-” “Multi-“ and “Two-“ Dose, though the single-dose regimen
AC

can be repeated if not successful the first time. The “Multi-Dose” methotrexate regimen has been

proposed for cases with higher -hCG levels (3000-5000), and the “Two-Dose” regimen may be

used when the -hCG level rises between Day 0 and Day 4 of the single-dose regimen.17, 20

Comparisons of single and non-single dose regimens show possibly more effectiveness with non-

single dose regimens, but this comes with more toxicity as well.21, 22
 ACCEPTED MANUSCRIPT

Surgical therapy is accomplished with laparoscopy, with laparotomy reserved for settings where

a skilled laparoscopic team is unavailable, or the patient has medical or surgical restrictions to

the laparoscopic approach. In the case of tubal ectopic, the pregnancy and its implantation site

can be removed completely with a unilateral salpingectomy. Alternatively, the tube can be

retained with a linear salpingostomy and extraction of the trophoblast. Less common ectopic

T
implantations (abdominal, ovarian, interstitial, cesarean section scar) may also be excised with

IP
the implantation site left in place. This risks incomplete removal of the pregnancy, but conserves

CR
pelvic organs.

US
Surgical management is first-line when there is any concern for tubal rupture or intraabdominal

bleeding. These include patients with hemodynamic instability, significant pain or peritoneal
AN
signs on exam, or evidence of moderate to large hemoperitoneum on ultrasound. It also should

be strongly considered if a patient’s ability to comply with frequent laboratory follow-up comes
M

into question. Patients who desire permanent sterilization may also prefer surgical removal of the

ectopic pregnancy, with ligation or removal of the contralateral tube to accomplish sterilization.
ED

Patients desiring rapid resolution of the ectopic pregnancy and a quick return to conception
PT

attempts may also prefer this approach. In general, cervical, cornual, abdominal, and cesarean

scar implantations are less amenable to safe surgical removal and should be referred to providers
CE

with expertise in their treatment.

AC

Expectant Management

Expectant management is an option for some patients with PUL, or even for some with

confirmed extrauterine pregnancies. This may be considered for hemodynamically stable,

asymptomatic patients whose -hCG levels are falling with serial assessments. Randomized

trials have shown this approach to be reasonable with -hCG levels up to 1500-2000 mIU/mL,
 ACCEPTED MANUSCRIPT

though up to 40% of women intending expectant management ultimately needed medical or

surgical treatment.23, 24 A fall in hCG level of at least 15-30% over 48 hours suggests that the

pregnancy is nonviable, regardless of location, which can justify withholding treatment. The

threshold hCG decline for considering expectant management depends on the initial level: A

30% drop is appropriate for a starting level of 2000 mIU/mL, 20% with a level of 500 mIU/mL,

T
and 15% when starting at 50 mIU/mL.12

IP
Some patients with tubal ectopic gestations will pass the pregnancy into the pelvis – an event

CR
sometimes termed a “tubal abortion.” These patients may experience sudden pain that quickly

US
improves, followed by a rapid drop in -hCG level. Complex fluid or blood may be visible on

pelvic ultrasound. It is essential to confirm that these patients have no ongoing bleeding, which
AN
may require a period of inpatient observation with serial examinations and laboratory

evaluations. Concern for bleeding often leads to laparoscopic evaluation for these patients.
M

However, if the pregnancy is identified free in the pelvis and removed, with no evidence of gross

tubal rupture or ongoing bleeding, it may be possible to manage these patients without tubal
ED

surgery or medical therapy. Postoperative methotrexate administration may be considered if

PT

there is any concern for residual trophoblastic tissue at the implantation site.

Patient Follow-up
CE

Laboratory Follow-up
AC

Patients with a PUL or ectopic pregnancy are generally followed until the -hCG level becomes

undetectable. Depending on the initial level and rate of fall, this may take many weeks.

Laboratory testing should continue weekly, with at least a 15% fall considered adequate. If at

any point the level fails to fall by 15% in one week, medical or surgical intervention should be
 ACCEPTED MANUSCRIPT

offered. Surgery should be the preferred option at this point with higher -hCG levels

(particularly if over 5,000 mIU/mL), the presence of a suspicious adnexal mass on imaging, or

the patient’s reluctance to continue with medical treatment and prolonged follow-up.

If the uterus was not evacuated prior to initial PUL treatment, then this should be performed if

T
the -hCG level fails to fall appropriately. Removal of an abnormal IUP may precipitate a rapid

IP
fall in serum hCG levels, while failure to observe this should prompt repeat medical or surgical

CR
ectopic pregnancy treatment.

Following surgical management of an ectopic pregnancy, follow-up of -hCG levels depends on

US
the likelihood of retained trophoblastic tissue. Patients who undergo removal of the pregnancy

with retention of the implantation site – such as with salpingostomy, resection of a cesarean scar
AN
implantation, or removal of a cervical or interstitial pregnancy – should have their -hCG levels
M

followed. Alternatively, if an entire pregnancy-containing fallopian tube is removed with

salpingectomy and confirmed histologically, laboratory follow-up is usually not necessary.

ED

Patient Counseling
PT

Though PUL evaluation and treatment focuses on laboratory testing, treatments, and the medical

risks of ectopic pregnancy, it is important to acknowledge the anxiety and loss that come with
CE

this process. Patients may fear an emergency hemorrhage while waiting for a diagnosis and

confirmed resolution of an ectopic pregnancy. Additionally, those diagnosed with ectopic

AC

pregnancies may feel the same sadness as any patient experiencing a miscarriage. Thus, it is

important to periodically assess patients’ wellbeing and support systems, and to offer formal

counseling to those in need.

Future Pregnancy
 ACCEPTED MANUSCRIPT

Many patients want to attempt a new conception as soon as they are cleared to do so. Intercourse

should be avoided while the -hCG level is detectable. If the patient was treated with

methotrexate she should postpone pregnancy until the medication is reliably cleared from her

system, and is advised to wait at least three months.17 This duration should also allow for tubal

healing and recanalization after salpingostomy or medical treatment. Patients treated with

T
complete surgical removal (salpingectomy) and no methotrexate may attempt pregnancy as soon

IP
as surgical healing is complete. While this duration is not clearly defined, 4-6 weeks should be

CR
generally safe.

US
Patients with a confirmed ectopic pregnancy should be counseled about the possibility of

recurrence. They should be advised to contact a healthcare provider as soon as a future

AN
pregnancy test becomes positive, and to again have PUL follow-up until the pregnancy’s location

is confirmed. History of ectopic pregnancy should be clearly documented in the patient’s medical
M

record.
ED

In many cases the exact location of the pregnancy may never be known, particularly when

expectant management or medical treatment without localization is used. Even when a uterine
PT

curettage returns with no evidence of an IUP an ectopic pregnancy has not been definitively

confirmed, especially if there are no signs of extrauterine location on imaging. Such patients
CE

should be counseled that the pregnancy’s location is uncertain, that it is statistically most likely
AC

to be intrauterine, and that this should be communicated to future pregnancy caregivers.

Conclusions

Pregnancy of unknown location can be a challenging clinical scenario, as false diagnosis can

lead to major patient harm. Careful consideration of individual patient risk, test interpretation,
 ACCEPTED MANUSCRIPT

and the harms of intervention versus expectant management must take place, and consultation

with experienced providers should occur when a diagnosis is in doubt. The choice of medical,

surgical or expectant management depends largely on the initial -hCG level. Ultimate treatment

choice should be individualized to a patient’s circumstances and preferences.

T
Disclosures

IP
The author reports no proprietary or commercial interest in any product mentioned or concept

CR
discussed in this article.

References

US
1. Marion LL, Meeks GR. Ectopic pregnancy: History, incidence, epidemiology, and risk factors. Clin

Obstet Gynecol 2012 Jun;55(2):376-86.

AN
2. Laing FC, Brown DL, Price JF, Teeger S, Wong ML. Intradecidual sign: is it effective in diagnosis of

an early intrauterine pregnancy? Radiology 1997 Sep;204(3):655-60.

M

3. Goldstein SR, Snyder JR, Watson C, Danon M. Very early pregnancy detection with endovaginal
ED

ultrasound. Obstet Gynecol 1988;72(2):200-4.

4. Tamai K, Koyama T, Togashi K. MR features of ectopic pregnancy. Eur Radiol 2007

PT

Dec;17(12):3236-46.

5. Ray JG, Vermeulen MJ, Bharatha A, Montanera WJ, Park AL. Association Between MRI Exposure
CE

During Pregnancy and Fetal and Childhood Outcomes. JAMA 2016 Sep 6;316(9):952-61.

6. Lindahl B, Ahlgren M. Identification of chorion villi in abortion specimens. Obstet Gynecol 1986
AC

Jan;67(1):79-81.

7. Insogna IG, Farland LV, Missmer SA, Ginsburg ES, Brady PC. Outpatient endometrial aspiration: an

alternative to methotrexate for pregnancy of unknown location. Am J Obstet Gynecol 2017

Aug;217(2):185 e1- e9.

 ACCEPTED MANUSCRIPT

8. Morse CB, Sammel MD, Shaunik A, Allen-Taylor L, Oberfoell NL, Takacs P, et al. Performance of

human chorionic gonadotropin curves in women at risk for ectopic pregnancy: exceptions to the rules.

Fertil Steril 2012 Jan;97(1):101-6 e2.

9. Barnhart KT, Simhan H, Kamelle SA. Diagnostic accuracy of ultrasound above and below the beta-

hCG discriminatory zone. Obstet Gynecol 1999;94(4):583-7.

T
10. Doubilet PM, Benson CB. Further evidence against the reliability of the human chorionic

IP
gonadotropin discriminatory level. J Ultrasound Med 2011 Dec;30(12):1637-42.

CR
11. Connolly A, Ryan DH, Stuebe AM, Wolfe HM. Reevaluation of discriminatory and threshold levels

for serum beta-hCG in early pregnancy. Obstet Gynecol 2013 Jan;121(1):65-70.

US
12. Barnhart KT, Sammel MD, Rinaudo PF, Zhou L, Hummel AC, Guo W. Symptomatic patients with an

early viable intrauterine pregnancy: HCG curves redefined. Obstet Gynecol 2004;104(1):50-5.
AN
13. Verhaegen J, Gallos ID, van Mello NM, Abdel-Aziz M, Takwoingi Y, Harb H, et al. Accuracy of

single progesterone test to predict early pregnancy outcome in women with pain or bleeding: meta-
M

analysis of cohort studies. BMJ 2012 Sep 27;345:e6077.

14. Schreiber CA, Creinin MD, Atrio J, Sonalkar S, Ratcliffe SJ, Barnhart KT. Mifepristone Pretreatment
ED

for the Medical Management of Early Pregnancy Loss. N Engl J Med 2018 Jun 7;378(23):2161-70.

15. Barnhart KT, Katz I, Hummel A, Gracia CR. Presumed diagnosis of ectopic pregnancy.[see
PT

comment]. Obstet Gynecol 2002;100(3):505-10.

16. Barnhart KT. Clinical practice. Ectopic pregnancy. N Engl J Med 2009;361(4):379-87.
CE

17. Practice Committee of American Society for Reproductive M. Medical treatment of ectopic

pregnancy: a committee opinion. Fertil Steril 2013 Sep;100(3):638-44.

AC

18. Lipscomb GH, McCord ML, Stovall TG, Huff G, Portera SG, Ling FW. Predictors of success of

methotrexate treatment in women with tubal ectopic pregnancies. N Engl J Med 1999 Dec

23;341(26):1974-8.

19. Doubilet PM, Benson CB, Frates MC, Ginsburg E. Sonographically guided minimally invasive

treatment of unusual ectopic pregnancies. J Ultrasound Med 2004 Mar;23(3):359-70.

 ACCEPTED MANUSCRIPT

20. Barnhart K, Hummel AC, Sammel MD, Menon S, Jain J, Chakhtoura N. Use of "2-dose" regimen of

methotrexate to treat ectopic pregnancy. Fertil Steril 2007 Feb;87(2):250-6.

21. Yuk JS, Lee JH, Park WI, Ahn HS, Kim HJ. Systematic review and meta-analysis of single-dose and

non-single-dose methotrexate protocols in the treatment of ectopic pregnancy. Int J Gynecol Obstet

2018;141(3):295-303.

T
22. Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a

IP
meta-analysis comparing "single dose" and "multidose" regimens. Obstet Gynecol 2003 Apr;101(4):778-

CR
84.

23. van Mello NM, Mol F, Verhoeve HR, van Wely M, Adriaanse AH, Boss EA, et al. Methotrexate or

US
expectant management in women with an ectopic pregnancy or pregnancy of unknown location and low

serum hCG concentrations? A randomized comparison. Hum Reprod 2013 Jan;28(1):60-7.

AN
24. Jurkovic D, Memtsa M, Sawyer E, Donaldson AN, Jamil A, Schramm K, et al. Single-dose systemic

methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled

M

randomized trial. Ultrasound Obstet Gynecol 2017 Feb;49(2):171-6.

ED

Table 1. Criteria for initiating a pregnancy of unknown location workup

PT

Positive Pregnancy Test plus Any of the Following:

Signs and Symptoms Significant Risk Factors
CE

 Acute pelvic pain  Prior confirmed ectopic pregnancy

 Vaginal bleeding  Known tubal damage (prior tubal
 Imaging shows hemoperitoneum with  surgery or pelvic inflammatory
AC

no IUP seen disease; known obstruction)

 Suspicious pelvic mass on imaging  Current use of intrauterine device
without definite EP or IUP  Pregnancy conceived with infertility
treatment
IUP = intrauterine pregnancy; EP = ectopic pregnancy
 ACCEPTED MANUSCRIPT

Table 2. Medical treatment regimens for ectopic pregnancies

Day “Single Dose” “Multi-Dose” “Two-Dose”

1  hCG  hCG  hCG

 Give Mtx 50 mg/m2  Give Mtx 1 mg/kg  Give Mtx 50 mg/m2

2  Give Lkv 0.1 mg/kg

T


IP
3 hCG
 Give Mtx 1 mg/kg if
< 15% fall from Day

CR
1
 If fall  15%, move to
Follow-up

4 

hCG 

US
Give Lkv 0.1 mg/kg  hCG
 Mtx 50 mg/m2 if
AN
hCG level rising

5  hCG

M

Give Mtx 1 mg/kg if

< 15% fall from Day
3
 If fall  15%, move to
ED

Follow-up

6  Give Lkv 0.1 mg/kg

PT

7  hCG: If fall  15%  hCG  hCG: If fall  15%

from Day 4, move  Give Mtx 1 mg/kg if  from Day 4, move to
CE

to Follow-up < 15% fall from Day Follow-up

 If fall insufficient,
consider second  5  If fall insufficient,
round of treatment
AC

 If fall  15%, move to  consider surgical

Follow-up management

8  Give Lkv 0.1 mg/kg

9  hCG
 ACCEPTED MANUSCRIPT

 If < 15% fall in hCG

from Day 7, consider
surgical management
 If fall  15%, move to
Follow-up

Follow-  Repeat hCG 7 days  Repeat hCG 7 days  Repeat hCG 7 days
up after appropriate after appropriate after appropriate
response confirmed response confirmed response confirmed

T
 If fall  15%, repeat  If fall  15%, repeat  If fall  15%, repeat

IP
every 7 days until every 7 days until every 7 days until
undetectable undetectable undetectable
  

CR
If fall insufficient, If fall insufficient, If fall insufficient,
consider second consider surgery consider surgery
round of treatment
or surgery

US
hCG = laboratory evaluation of quantitative serum -hCG
Mtx = methotrexate IM injection
AN
Lkv = leucovorin IM injection
M
ED
PT
CE
AC