Ultrasound in Early

P re g n a n c y
Viability, Unknown Locations, and Ectopic
Pregnancies

a, b,c
Emily W. Scibetta, MD *, Christina S. Han, MD

KEYWORDS
 Ectopic pregnancy  Gestational sac  Miscarriage  Early pregnancy loss
 Pseudosac

KEY POINTS
 Despite significant advances in early obstetric ultrasound, complications of ectopic preg-
nancy still account for 6% of all maternal deaths in the United States and remain the lead-
ing cause of maternal death secondary to hemorrhage.
 Ultrasound is critical in the evaluation and management of early pregnancy loss, preg-
nancy of unknown location, and ectopic pregnancies. In some cases, both transabdomi-
nal and transvaginal routes should be used for complete evaluation.
 In an asymptomatic woman with early pregnancy, there is no demonstrated benefit in
routine screening for ectopic pregnancy. Evaluation for cesarean scar pregnancies should
be considered in women with a previous cesarean delivery.
 The sensitivity of transvaginal ultrasonography for the diagnosis of ectopic pregnancy
ranges from 73% to 93% and depends on the gestational age and the expertise of the
ultrasonographer.
 Diagnostic criteria for early pregnancy loss have expanded in recent years to ensure false
positive results do not lead to inappropriate evacuation of desired pregnancies. The pa-
tient, her desire to continue pregnancy, and her willingness to postpone interventions
must be included in the diagnostic process and decision making to individualize these
guidelines to patient circumstances.

Disclosures: The authors have nothing to disclose.

a
Department of Obstetrics and Gynecology, Harbor-UCLA, 1000 W Carson St, Torrance, CA
90509, USA; b Division of Maternal-Fetal Medicine, University of California at Los Angeles,
10833 Le Conte Avenue, Room 27-139 CHS, Los Angeles, CA 90095-1740, USA; c Center for Fetal
Medicine and Women’s Ultrasound, 6310 San Vicente Boulevard, Suite 520, Los Angeles, CA
90048, USA
* Corresponding author. 300 Hillmont Avenue, Ventura, California 93003.
E-mail address: Emily.scibetta@gmail.com

Obstet Gynecol Clin N Am 46 (2019) 783–795

https://doi.org/10.1016/j.ogc.2019.07.013 obgyn.theclinics.com
0889-8545/19/ª 2019 Elsevier Inc. All rights reserved.
784 Scibetta & Han

INTRODUCTION

A pregnancy of unknown location (PUL) is defined by a positive beta-subunit of the hu-

man chorionic gonadotropin (b-hCG) test with no clear evidence of either an intrauter-
ine or an ectopic pregnancy on transvaginal ultrasound. The differential diagnosis in
PUL includes early, normal intrauterine pregnancy, early pregnancy loss, and ectopic
pregnancy. Up to 25% of identified pregnancies will end in early pregnancy loss, and
1% to 2% will be ectopic pregnancy.1
These 3 diagnoses have been increasingly inserted into the political discourse on
reproductive rights over the past decade, but it is important to remember that in the
clinical setting, accurate diagnosis and prompt management of acute situations,
such as ectopic pregnancies, are integral in decreasing morbidity and mortality of
the woman. Despite significant advances in early obstetric ultrasound, complications
of ectopic pregnancy still account for 6% of all maternal deaths in the United States
and remain the leading cause of maternal death secondary to hemorrhage.1,2 Early
identification and appropriate surveillance in these women to rule out ectopic preg-
nancy are critical to decreasing maternal mortality and are the primary focus of this
article.

NORMAL EARLY PREGNANCY

Early diagnosis of a normal intrauterine pregnancy is best established with transvagi-

nal ultrasonography with an empty maternal bladder. Approximately 1 week after fertil-
ization, the blastocyst should implant eccentrically in 1 side of the uterine decidua,
although this structure is not yet visible on ultrasound. A small, anechoic, well-
circumscribed fluid collection known as a gestational sac can be identified by 4 to
5 weeks’ gestation with transvaginal ultrasound (Fig. 1A). The normal gestational
sac measures only 2 to 3 mm in the fifth week of pregnancy. The sac is typically sur-
rounded by 2 concentric echogenic rims known as the double decidual sign (Fig. 1B).
An early intrauterine pregnancy can be confirmed on 2-dimensional ultrasound with
the identification of a bright, echogenic ring with anechoic center, known as the “yolk
sac” (Fig. 1C). The yolk sac is typically present by the fifth week of gestation. The
embryo is often visible by 6 weeks of gestation. It can be seen on transvaginal ultra-
sonography as a linear echogenic structure adjacent to the yolk sac (Fig. 1D). A mea-
surement of the embryo or “fetal pole” from crown to rump confirms the gestational
age of the pregnancy. Fetal cardiac activity should be noted by 6 to 7 weeks’ gesta-
tional age. Table 1 shows the progression of normal early pregnancy findings and
associated gestational ages.

EARLY PREGNANCY LOSS: DIAGNOSTIC CRITERIA

Early pregnancy loss is defined as a nonviable pregnancy at less than 13 weeks’

gestation identified by appropriate size criteria, such as a fetal pole without cardiac
activity, or loss of normal ultrasound finding progression on transvaginal imaging.3,4
Early pregnancy loss occurs after 25% of positive pregnancy tests and at least 10%
of clinically recognized pregnancies.5 More than 80% of spontaneous pregnancy
loss occurs before 12 weeks’ gestation.6 Of these early losses, 50% are anembryonic
gestations.6 Of the remaining embryonic early pregnancy loss, another 40% to 50%
have been attributed to aneuploidy.7
In desired pregnancies, it is critical to ensure appropriate criteria have been met
before offering intervention to avoid undesired loss of a viable pregnancy, or missed
diagnosis of other pregnancy complications, such as ectopic, molar pregnancy, birth
 Ultrasound in Early Pregnancy 785

Fig. 1. Early normal pregnancies. (A) Early gestational sac located in an eccentric position in
the decidua, (B) double decidual sign, (C) gestational sac with echogenic well-circumscribed
yolk sac, and (D) fetal pole seen adjacent to a yolk sac.

defects, or cesarean scar pregnancy. When pregnancy loss is suspected, but not
confirmed, it is appropriate to offer follow-up imaging in 7 to 10 days, or sooner if clin-
ical picture evolves (ie, worsening bleeding or pain). If pregnancy loss is reliably
confirmed, the patient can be definitively counseled on the diagnosis of pregnancy
loss and offered management options, such as expectant management, prosta-
glandin and mifepristone administration, or surgical evacuation. Detailed discussion
of management options is beyond the scope of this article.

Ultrasound Findings
Ultrasound is the preferred modality for diagnosis of early pregnancy loss. Diag-
nostic criteria for early pregnancy loss have expanded in recent years to ensure

Table 1
Progression of early normal pregnancy findings

Gestational Age at Diagnosis by

Transvaginal Ultrasound, wk
Gestational sac 5
Yolk sac 5–6
Fetal pole 6
Cardiac activity 6–7
786 Scibetta & Han

false positive results do not lead to inappropriate evacuation of desired pregnan-

cies. The criteria discussed in this article were defined by Doubilet and col-
leagues,8,9 on behalf of the Society of Radiologists in Ultrasound Multispecialty
Panel on Early First Trimester Diagnosis of Miscarriage and Exclusion of a Viable In-
trauterine Pregnancy and endorsed by the American College of Obstetricians and
Gynecologists (ACOG). In order to achieve a specificity approaching 100%, diag-
nostic criteria for early pregnancy loss, as defined by these organizations, include
increasingly conservative criteria, which can be applied indiscriminately to all ultra-
sound facilities. It is important to note that ACOG encourages practitioners to indi-
vidualize their counseling and diagnosis of early pregnancy loss to meet an
individual patient’s needs, including the woman’s desire to continue the pregnancy;
her willingness to postpone intervention to achieve 100% certainty of failure of preg-
nancy; and the potential consequences of waiting for intervention, including un-
wanted spontaneous passage of pregnancy tissue, the need for an unscheduled
visit or procedure, and patient anxiety. A shared decision-making model, engaging
the patient and provider in a discussion of risks, benefits, and patient priorities,
should be used in the diagnostic process and decision making to individualize these
guidelines to patient circumstances.3
Early pregnancy loss can be subdivided into anembryonic and embryonic gesta-
tions. Anembryonic gestation is defined as an enlarged gestational sac with no visu-
alization of fetal pole. The diagnostic criteria for anembryonic gestation require a
mean sac diameter (MSD) greater than or equal to 25 mm on transvaginal ultra-
sound3,10 (Fig. 2A). Embryonic demise is defined as a sufficiently sized fetal pole
with no cardiac activity visualized (Fig. 2B). Although cardiac activity is widely
accepted to be visible once the linear fetal pole can be seen, the size necessary to
definitively rule out cardiac activity has expanded over the years. For many years,
5 mm was considered an appropriate cutoff for identification of cardiac activity. How-
ever, a 2011 metaanalysis showed that the small sample size in initial studies was not
sufficient to establish specificity greater than 90%.11 In addition, an interobserver
variability of up to 15% on crown-rump-length measurements identified by Pexsters
and colleagues12 suggests the less stringent criteria were warranted.10 Following
these studies, new criteria for crown-rump length greater than or equal to 7 mm
were established. Additional sonographic criteria for diagnosis of early pregnancy
loss are listed in Box 1.

Fig. 2. Early pregnancy loss. (A) An empty gestational sac measuring >25 mm MSD with no
yolk sac or fetal pole and (B) an embryo with no fetal cardiac activity seen on Doppler im-
aging. UT, uterus.
 Ultrasound in Early Pregnancy 787

Box 1
Ultrasound criteria for diagnosis of early pregnancy loss

Enlarged gestational sac with no embryo: MSD 25 mm

Embryo with no cardiac activity: crown-rump length 7 mm
Absence of embryo with heartbeat 14 days or more after ultrasound confirming gestational sac
WITHOUT yolk sac
Absence of embryo with heartbeat 11 days or more after ultrasound confirming gestational sac
WITH yolk sac
Empty uterine cavity in patient with vaginal bleeding and previously confirmed intrauterine
pregnancy by at least gestational sac and yolk sac

Adapted from Early Pregnancy Loss. Practice Bulletin No. 150. American College of Obstetri-
cians and Gynecologists. Obstet Gynecol 2015;125:1258-67; and Rodgers SK, Chang C, DeBarde-
leben JT, et al. Normal and Abnormal US Findings in Early First-Trimester Pregnancy: Review of
the Society of Radiologists in Ultrasound 2012 Consensus Panel Recommendations. Radio-
graphics 2015;35(7):2135-48.

PREGNANCY OF UNKNOWN LOCATION AND ECTOPIC PREGNANCY

Ectopic pregnancy is defined as a pregnancy implanted in a location other than the

endometrial cavity. The most common location is tubal, which can be further classified
as fimbrial, ampullary, or isthmic (Fig. 3A, B). Five percent to 10% of nonuterine preg-
nancies implant outside the tube, including the ovary, interstitium, cervix, peritoneal
cavity, rudimentary uterine horns (also known as cornual), or cesarean section scar.
In incredibly rare cases, posthysterectomy pregnancies have been described.10
Appropriate management of suspected ectopic pregnancy must balance an incorrect
early diagnosis that leads to disruption of a normal, desired intrauterine pregnancy
against the risk of delayed confirmation of ectopic pregnancy with increased morbidity
and mortality in the patient with a rupture of the ectopic pregnancy.

Epidemiology of Ectopic Pregnancy

Approximately 2% of pregnancies in the United States are ectopic.1 The actual burden
of disease is difficult to confirm because the Centers for Disease Control and Preven-
tion tracking does not account for outpatient management of cases, but it appears the

Fig. 3. Tubal pregnancies. (A) Early tubal ectopic pregnancy and (B) advanced tubal ectopic
pregnancy in late first trimester. RO, right ovary.
788 Scibetta & Han

overall burden of disease has been stable over recent decades.2,13 Tubal ectopic
pregnancy remains a significant risk for maternal death and morbidity. It is still the
main cause of pregnancy-related death owing to hemorrhage. Overall, tubal preg-
nancy accounts for a surprising 6% of maternal deaths in the United States.2,14
The risk of recurrence of ectopic pregnancy is approximately 10% in women with 1
prior ectopic pregnancy and as high as 25% with 2 or more prior ectopic pregnan-
cies.15 Heterotopic pregnancy, defined as an intrauterine gestation with concurrent
ectopic pregnancy, carries a natural incidence of 1 in 30,000, but assisted reproduc-
tive technology (ART) has increased the incidence to 1 in 7000 after ovulation induc-
tion.16 This risk is considered even higher after in vitro fertilization, with incidence
documented as high as 1 case per 100 for women who underwent in vitro fertiliza-
tion.17 Additional risk factors for ectopic pregnancy are listed in Table 2.

Pathophysiology
Risk factors for tubal pregnancy include any exposure that could damage the fallopian
tubes, such as prior ectopic pregnancy, prior tubal surgery, history of pelvic inflamma-
tory disease, and salpingitis node isthmica. Other risk factors include smoking, endo-
metriosis, abdominal surgery, smoking, history of sexually transmitted infection,
endometriosis, in utero exposure to diethylstilbestrol, and the use of ART. Although
pregnancy risk is low with intrauterine devices (IUD) in place, if a pregnancy occurs
with an IUD in situ, the risk of ectopic pregnancy is much higher. Approximately
50% of patients with ectopic pregnancy carry no known risk factors. Thus, a high in-
dex of suspicion is warranted in any woman of reproductive age who presents with
abdominal pain, vaginal bleeding, or evidence of hemodynamic instability.

Pregnancy of Unknown Location: Clinical Evaluation

Up to one-half of all pregnant women have signs and symptoms, such as pain or
bleeding, that are suggestive of early pregnancy loss in the first trimester.18 Every pa-
tient with early pregnancy bleeding and/or abdominal pain should be evaluated with
the goal of early identification of ectopic pregnancy. There is no demonstrated benefit
in screening asymptomatic, clinically stable women for ectopic pregnancy.19 Consid-
eration can be made for screening for cesarean scar pregnancies in women with 1 or
more prior cesarean deliveries (see Ilan E. Timor-Tritsch and colleagues’ article,
“Cesarean Scar Pregnancy: Diagnosis and Pathogenesis,” and Ilan E. Timor-Tritsch

Table 2
Risk factors for ectopic pregnancy

Major Risk Factors Minor Risk Factors

History of tubal surgery, including reconstructive Endometriosis
surgery and tubal sterilization Previous abdominal
In utero exposure to diethylstilbestrol surgery
ART Tobacco smoking
IUDs
History of pelvic inflammatory disease
Previous ectopic pregnancy
Salpingitis nodosa isthmica
History of tubal sterilization

Adapted from Baltarowich OH, Scoutt LM. Ectopic Pregnancy. In: Norton ME, Scoutt LM, Feldstein
VA, editors. Callen’s Ultrasonography in Obstetrics and Gynecology, 6th edition. Philadelphia:
Elsevier; 2017; with permission.
 Ultrasound in Early Pregnancy 789

and colleagues’ article, “Cesarean Scar Pregnancy: Patient Counselling and

Management,” in this issue).
Initial management depends on the clinical stability of the patient and thorough his-
tory and physical examination. For patients who present with a positive pregnancy
test, signs of shock, and evidence of intraabdominal bleeding, immediate surgical
management is warranted. In these cases, patients may present with rebound tender-
ness on abdominal examination, hypotension, tachycardia, and evidence of free fluid
on ultrasound. Ultrasound identification of free fluid is best established by FAST
(focused assessment with sonography in trauma) scan to identify fluid in the pericolic
gutters and posterior cul-de-sac. Occasionally, an ectopic pregnancy with chronic
insidious bleeding will appear as organized, expansive clot on ultrasound. With appro-
priate surgical training, urgent surgical management is often accomplished with lapa-
roscopy. Some resource-limited settings may call for exploratory laparotomy.
For stable patients, quantitative serum b-hCG levels combined with transvaginal ul-
trasound assessment is the standard of care. Approximately 40% of ultrasounds at
first presentation in symptomatic first-trimester patients will be inconclusive because
of a failed pregnancy before development of a gestational sac or because the preg-
nancy is too early to be readily identified.20 Because of this, triaging patients into
appropriate categories for expedited follow-up is critical.

Clinical Evaluation: Role of Ultrasound

Ultrasound is critical in the diagnosis of PUL. Appropriate understanding of normal
signs in early intrauterine pregnancy and early pregnancy loss is important to rule
out ectopic pregnancy. With reliable pregnancy dating, transvaginal ultrasonography
should identify normal intrauterine pregnancies by 5.5 weeks of gestation close to
100% of the time.21
A standardized protocol should be implemented in each ultrasound laboratory.
Given the known common locations for nonintrauterine pregnancies, the protocol
for evaluation of patient with PUL should include clear imaging of the uterus (including
bilateral cornua), cervix, bilateral ovaries and tubes, cul-de-sac, and nearby pelvic
structures. Both transabdominal and transvaginal imaging may be necessary to eval-
uate the pelvis and lower abdomen adequately.
Clear evidence of ectopic pregnancy on ultrasound relies on characteristic extra-
uterine findings combined with no clear evidence of an intrauterine gestation except
in a heterotopic pregnancy. These findings include a nonhomogenous mass separate
from the ovary with or without a hyperechoic “ring sign” or a fetal pole with or without
cardiac activity in an extrauterine location. Literature suggest that more than 60% of
ectopic pregnancies present as a nonhomogenous mass separate from the ovary;
approximately 20% present as a hyperechoic ring, and 13% will present with an
obvious gestational sac, with or without a fetal pole.22 Ectopic placental blood flow,
commonly referred to as a ring of fire, can be seen with color Doppler within the pe-
riphery of an adnexal mass. This hypervascularity can be difficult to distinguish from
typical findings in a corpus luteum, and thus, distinct diagnosis can be difficult.6
The sensitivity of transvaginal ultrasonography for the diagnosis of ectopic pregnancy
ranges from 73% to 93% and depends on the gestational age and the expertise of the
ultrasonographer.18
If there is identification of a hypoechoic fluid collection without the double decidual
sign or without clear identification of a yolk sac, commonly referred to as a pseudosac,
an ectopic pregnancy cannot be ruled out. This pseudosac is often distinguished from
a gestational sac by its midcavity position (as opposed to eccentric placement), lack of
double decidual sign or yolk sac, and teardrop shape (Fig. 4A).
790 Scibetta & Han

Fig. 4. Potential nonpregnancy findings in ectopic pregnancies. (A) A pseudosac in decidua

and (B) a free fluid in the cul-de-sac. FF, free fluid; L, left; RT, right.

Although a scant amount of intraperitoneal fluid can be normal, significant intraab-

dominal fluid raises the suspicion for hemoperitoneum and thus adds diagnostic utility
(Fig. 4B). Hemoperitoneum can be hypoechoic or of mixed echogenicity, evolving to
become more hyperechoic as the clot organizes. Bleeding typically collects in gravity-
dependent regions, most commonly in the cul-de-sac on pelvic imaging, where as lit-
tle as 50 mL can be appreciated. Additional imaging of the pericolic gutters and pouch
of Morrison near the liver can confirm the presence of significant intraabdominal
bleeding that has overwhelmed the pelvis. Imaging via both the transabdominal and
the transvaginal routes can also elicit peritoneal signs in cases of intraabdominal
bleeding, with guarding and rebound tenderness on transabdominal imaging and cer-
vical motion tenderness on transvaginal imaging.
Nontubal locations of ectopic pregnancy, including interstitial, cornual, ovarian,
cervical, abdominal, and cesarean scar, account for approximately 5% of all
ectopic pregnancies. Ultrasound findings in these cases are widely variable
(Fig. 5A–D).
Interstitial pregnancies develop in the proximal fallopian tube immediately adjacent
to the uterine myometrium (see Fig. 5A). The expansibility of this space allows the
pregnancies to progress to later gestations than typical distal tubal pregnancies
before rupturing. However, if rupture does occur, patients experience significantly
greater blood loss and morbidity, with mortalities quoted as high as 2.5%.6 Evaluation
for a suspected interstitial pregnancy begins by identifying the interstitial segment of
the tube, located in the transverse plane at the level of the uterine fundus. This
segment is seen as a thin echogenic line extending from the lateral aspect of the endo-
metrial cavity through the myometrium toward the uterine serosa.15 An abnormal inter-
stitial ectopic pregnancy is located within this line (see Fig. 5B), compared with a
normal intrauterine pregnancy, which would be located medial to the line.
Cornual pregnancies specifically refer to a pregnancy implanted in a rudimentary
horn of a patient with a Mullerian anomaly. Interstitial and cornual pregnancies can
mirror the appearance of an eccentrically implanted gestational sac, making diagnosis
by ultrasound challenging. Three ultrasound criteria for diagnosis of interstitial or
cornual pregnancies include (1) empty uterine cavity, (2) a gestational sac separate
from an empty endometrial cavity and greater than 1 cm distant from most lateral
edge of uterine cavity, and (3) a thin less than 5 mm myometrial mantle surround
the gestational sac.23 Three-dimensional (3D) ultrasound can be invaluable in distin-
guishing a cornual or interstitial from an eccentric intrauterine pregnancy and is dis-
cussed later.
 Ultrasound in Early Pregnancy 791

Fig. 5. Nontubal ectopic pregnancies. (A) An interstitial ectopic pregnancy, (B) interstitial
line sign connecting the interstitial ectopic pregnancy, (C) ovarian ectopic pregnancy, and
(D) cervical ectopic pregnancy. ANT, anterior; LO, left ovary; LT ADN, left adnexa; SAG UT,
sagittal uterus.

Abdominal pregnancies are rare and defined as an intraperitoneal implantation

separate from a pelvic organ location. The presentation of abdominal pregnancy is
widely varied, nonspecific, and dependent on the gestational age at diagnosis.
Some ultrasound findings include oligohydramnios (common, but nonspecific) and
lack of myometrium surrounding fetus. A transabdominal scan with a full maternal
bladder is very helpful in establishing the diagnosis. MRI may also be helpful as an
adjunct in identifying implantation site in an abdominal pregnancy.
Ovarian pregnancies are difficult to distinguish from tubal ectopics by ultrasound, but
may be diagnosed by the identification of ovarian cortex surrounding or contiguous with
a mass that is suspicious for ectopic pregnancy (see Fig. 5C). Intraperitoneal fluid sug-
gestive of hemoperitoneum may increase the index of suspicion, but can also represent
a ruptured hemorrhagic cyst. Diagnosis is typically made surgically and even then can
be difficult to distinguish on direct visualization from a bleeding corpus luteum cyst.
Cervical ectopic pregnancies are often diagnosed by transvaginal imaging, specu-
lum examination, and palpation. The more cephalad the implantation, the greater the
risk of bleeding in cervical ectopic pregnancies given their increased capacity to
expand. Ultrasound findings may include an hourglass uterine shape with ballooning
of the cervical canal, gestational tissue at the level of the cervix with no evidence of
intrauterine gestational tissue, and a bridge of endocervical canal visualized between
the empty endometrial canal and the cervical pregnancy6 (see Fig. 5D). It is important
to distinguish a cervical ectopic from an aborting conceptus or a cesarean scar preg-
nancy, because management of these 3 diagnoses are very different. A suction
792 Scibetta & Han

curettage in an unexpected cervical ectopic pregnancy or cesarean scar pregnancy

can result in unexpected hemorrhage. Color Doppler will show copious peritropho-
blastic flow in a cervical or cesarean scar pregnancy, whereas a pregnancy in transit
through the cervical canal will have decreased flow.

Clinical Evaluation: Role of Three-Dimensional Ultrasound

3D imaging may play an integral role in differentiating between normal and eccentri-
cally located pregnancies, particularly in cases of abnormal uterine cavity (such as
Mullerian abnormality or leiomayomatous uterus) and suspected interstitial, corneal,
or cesarean scar pregnancies. In these cases, the ability to render multiple planes
and postprocess an image allows for more exact localization of the suspected preg-
nancy relative to the endometrial cavity, as shown in Fig. 6.17,19,24,25 3D ultrasound is
preferred over MRI because of lower cost and accessibility.

Clinical Evaluation: Role of Quantitative b-Human Chorionic Gonadotropin

Without definitive evidence of ectopic pregnancy on ultrasound, it is inappropriate to
manage PUL with only 1 b-hCG measurement. The common practice is to rule out
normal intrauterine pregnancy based on a discriminatory zone in b-hCG measurement
above which pregnancy should be identified transvaginally. This ultrasound evaluation
is often coupled with an anticipated increase in b-hCG of at least 53% in 48 hours. The
appropriate discriminatory zone has been expanded in recent years to avoid disrup-
tion of a normal intrauterine pregnancy in stable patients. ACOG generally accepts
3500 mIU/mL as the appropriately conservative level.13

Pregnancy of Unknown Location: Summary of Surveillance Strategies

Conservative management with close follow-up is appropriate in women with PUL if
they are clinically stable and have sufficient support in their life to follow up in clinic
in 2 days and have safe, swift access to emergency facilities. A reasonable manage-
ment strategy includes the following:
1. Obtain serum quantitative b-hCG levels on 2 occasions, 48 hours apart, sent to the
same commercial laboratory. In a normal intrauterine pregnancy, serum b-hCG
levels are expected to increase at least 53% to 66% over 48 hours.26–28 An

Fig. 6. Demonstration of utility of 3D ultrasound imaging. (A) Two-dimensional imaging at

the level of the fundus in the transverse view with the sac seen to be located in the cornua
without contiguity with the endometrial cavity. (B) 3D rendering of the same uterus in the
coronal view revealing intact myometrium surrounding the normally located gestational sac
located lateral to the uterine septum.
 Ultrasound in Early Pregnancy 793

increase of less than 53% over 48 hours without definitive evidence of intrauterine
pregnancy on pelvic ultrasound is suspicious for early pregnancy failure or ectopic
pregnancy.
2. If b-hCG increases greater than 53% over 48 hours with a level greater than 3500
mIU/mL and there is still no evidence of intrauterine pregnancy, ectopic pregnancy
is highly likely.
3. If no evidence of intrauterine pregnancy or ectopic pregnancy is identified after
48 hours and b-hCG is falling in a clinically stable patient, it is reasonable to
continue expectant management because early intrauterine pregnancy loss
cannot be excluded and methotrexate can be avoided. In a recent study evaluating
expectant management in suspected ectopic pregnancy with b-hCG less than
2000 mIU/mL, there was no statistically significant difference in treatment success
when methotrexate was compared with expectant management.29
The detailed management of ectopic pregnancies is not covered in this article,
because it is outside the scope of an ultrasound volume. For the nonobstetrician im-
aging provider, it is, however, important to remember that ACOG recommends that
Rhesus-D–negative patients with any form of early pregnancy loss receive anti-
Rh(D) immunoglobulin.13

Role of Novel Biomarkers in Pregnancy of Unknown Location

A significant focus of recent clinical inquiry has been on modeling novel serum bio-
markers for early pregnancy outcomes. The goal has been to determine if biomarkers
may be able to aid in determining the location or viability of an early gestation. The
hope has been that these studies could aid in determination of best treatment plans.24
As reviewed above, in the absence of clear ultrasound evidence of an extrauterine
gestation with elevated hCG, a firm diagnosis of ectopic pregnancy currently relies on
serial b-hCG levels and usually multiple pelvic ultrasounds. Much to the continued
frustration of gynecologists everywhere, ultrasound at first presentation of symptom-
atic women in early pregnancy is inconclusive in up to 40% of women. Although oper-
ator experience plays a major role, this is likely because the gestation is too early to be
clearly identified or an early pregnancy loss has occurred with collapse of the gesta-
tional sac. Given the limited role of ultrasound at initial diagnosis in stable patients, the
pursuit of novel biomarkers has intensified to prevent the morbidity of bleeding, infer-
tility, or death of delayed diagnosis of ectopic pregnancy.
Novel markers of interest include ratio of b-hCG of day 0 and day 2, Activin A,
pregnancy-associated plasma protein-A, pregnancy-specific beta-glycoprotein 1,
metalloprotease-12, nucleic acid markers, markers of corpus luteal function, angio-
genesis markers, endometrial function markers, and multiple marker tests. Despite
the promise of many of these tests, prospective cohort studies of PUL will be required
to validate these tests independently to the point of incorporation into clinical care.20

SUMMARY

Ultrasound is the primary tool in the evaluation and management of PUL. The practi-
tioner must keep in mind the differential diagnoses of early pregnancy loss, PUL, and
ectopic pregnancies. Both transabdominal and transvaginal ultrasounds should be
available, in addition to physical examination, for complete evaluation. Diagnostic
criteria for early pregnancy loss have expanded in recent years to ensure false positive
results do not lead to inappropriate evacuation of desired pregnancies. A shared
decision-making model, engaging the patient and provider in a discussion of risks,
794 Scibetta & Han

benefits, and patient priorities should be used in the diagnostic process and decision
making to individualize these guidelines to patient circumstances.

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