First-Trimester Ultrasound: A Comprehensive Guide

16. Ectopic Pregnancy: Pregnancy of Unknown Location (PUL)

Linda Do  and James M. Shwayder 

(1)

Department of Obstetrics and Gynecology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA

Linda Do

Email: ldo@umc.edu

James M. Shwayder (Corresponding author)

Email: jshwayder@umc.edu

Keywords

Ectopic pregnancyHeterotopic pregnancyInterstitial pregnancyIntrauterinePregnancyPregnancy of unknown location (PUL)Human chorionic gonadotropin (hCG)

Introduction

Ectopic pregnancy (EP) represents 1–2 % of pregnancies [1]. They have a risk of rupture, hemorrhage, and tubal damage, which can lead to decreased future fertility and even death. The most common presenting symptoms suggesting an EP are abdominal pain or vaginal bleeding. Advances in ultrasound technology allow the detection of ectopic pregnancies in their earliest state, allowing treatment alternatives, e.g., medical therapy or surgical treatment, and reduced morbidity and mortality. However, immediate diagnosis is not always accomplished. Thus, a systematic approach to patients with a possible EP is required to avoid interruption or mistreatment of an intrauterine pregnancy (IUP), timely diagnosis of an EP, and appropriate management with pregnancy failure. This chapter reviews such an approach emphasizing the value of various diagnostic tests.

Pregnancy of Unknown Location

Pregnancy of unknown location (PUL) describes a situation in patients with a positive pregnancy test when transvaginal ultrasound (TVS) fails to identify a pregnancy’s location, either intrauterine or extrauterine. In patients with a positive urinary pregnancy test, the location of a pregnancy is usually confirmed in more than 90 % of cases [2]. The remainder is categorized as a PUL [3]. In 2011, Barnhart et al. reviewed the consensus nomenclature associated with early pregnancy evaluation, categorizing such pregnancies into the following descriptive areas [4]:

·               Definite ectopic pregnancy,

·               Probable ectopic pregnancy,

·               Pregnancy of unknown location,

·               Probable intrauterine pregnancy, or

·               Definite intrauterine pregnancy.

The earliest sign of pregnancy is the finding of a sac-like structure, regardless of location. The finding of such a structure in the uterus is considered a probable IUP. This same finding in the adnexa is consistent with a probable EP. The finding of a yolk sac within a gestational sac definitively diagnoses a pregnancy, regardless of location. The finding of a gestational sac with a yolk sac in the uterus is consistent with a definite IUP, while this same finding outside of the uterus definitely diagnoses an EP. A PUL exists when there are no signs of either an IUP or an EP, which represents ~10 % of cases [5]. Expectant management with TVS and hCG will lead to the diagnosis of a visualized IUP (34.3 %) or EP (8.7 %), with a resolved PUL in 56.9 % of these patients [5]. Thus, patients who are clinically stable with a PUL should be managed expectantly [3]. A small number of patients will remain with a PUL, which can be treated medically, surgically, with a diagnostic dilatation and curettage, or observed for spontaneous resolution [4].

A consensus regarding follow-up surveillance of patients with a PUL has not been obtained. Individualized surveillance based on risk factors could lead to more accurate diagnosis and reduced cost. Barnhart et al. retrospectively assessed specific clinical factors to determine the frequency and immediacy of follow-up for patients with a PUL [6]. They created a scoring system to triage women into various risk groups. Those at age “extremes” were assigned increasing risk scores: age < 18 received a +1 and age > 38 assigned a +3. Prior EP increased a patients risk, with those having one prior EP assigned +2, whereas those with 2 or more prior EP were assigned +3. Patients with bleeding were assigned +4. Patients with a prior miscarriage or with a hCG > 2000 mIU/mL were assigned −1. A patient’s risk for a nonviable gestation was stratified into low risk (−2 to −1), intermediate risk (0 to +4), and high risk (equal to or greater than +5) based on the total score. Based on their risk stratification, patients received surveillance as follows:

·               low-acuity surveillance: “send home” with follow-up in 4–7 day

·               standard surveillance; “monitor” with repeat hCG in 2 days, or

·               high-acuity surveillance: “intervention” including uterine evacuation, laparoscopy, or surveillance in 24 h, depending on the patient’s clinical status.

Overall, the proposed scoring system had a >90 % specificity. Thus, clinical signs and symptoms of a woman with PUL may help optimize surveillance plans.

Condous et al. developed a logistic regression model using serial hCG and progesterone levels, drawn 48 h apart, to predict the outcome of PULs. A hCG increase of >66 % was predictive of an IUP with a positive predictive value (PPV) of 96.5 %. A serum progesterone of <20 mmol/l predicted a failing PUL with a PPV of >95 %. In summary, the change in hCG outperformed serum progesterone change in predicting the location and outcome of a PUL.

One can postulate that combining the results of these two studies would improve our surveillance of patients with PUL. Specifically, individualized risk assessment, correlated with serial hCG levels, and complimented with ultrasound and, in select cases, serum progesterone will help determine the ultimate outcome of PULs.

Human Chorionic Gonadotropin (hCG) Dynamics

Human chorionic gonadotropin (hCG) can be qualitatively assessed resulting in a positive or negative result. However, measuring the quantitative hCG level in the blood is quite useful if the initial pregnancy evaluation is inconclusive. One can follow serial hCG levels, using the rationale that abnormally rising levels are more consistent with either an EP or a failed IUP. Older studies determined that the 2-day rise of hCG in a normal pregnancy is at least 66 % [7]. A more recent 2004 study determined that the 2-day rise hCG (normal pregnancy) ranged between 1.53 and 3.28 times, with a median of 2.24 times [8]. The premise is that an ectopic pregnancy will have an inadequate rise in the hCG level over 2 days, as only 21 % of EPs will have a rise of 53 % or more [9]. An often overlooked finding of the earlier study was that 15 % of normal pregnancies also had abnormal hCG increases. Thus, abnormally rising hCG levels are not diagnostic of an ectopic pregnancy, only highly suggestive. Abnormal increases in hCG values should raise one’s index of suspicion for an ectopic pregnancy or an abnormal intrauterine pregnancy. TVS is valuable, regardless of hCG increase, to determine the location and status of the pregnancy.

Threshold and Discriminatory Levels of hCG

Threshold Level

The threshold level is the lowest level of hCG at which a normal intrauterine pregnancy can be detected, typically visualizing an early gestational sac. Older studies proposed a threshold value of 1000 mIU/mL [10]. However, advances in ultrasound technology have improved our imaging capabilities. Thus, more recent studies indicate the threshold level may be as low as 390 mIU/mL [11].

Discriminatory Level

The discriminatory level is that level of hCG above which all normal (singleton) intrauterine pregnancies should be seen. This level typically ranged between 1000 and 1500 mIU/mL in most laboratories. The discriminatory level or value, however, has undergone revision, based on two key studies. Doubilet and Benson reviewed a decade of experience in patients with TVS and hCG done on the same day [12]. They identified those patients whose initial TVS did not visualize an intrauterine fluid collection, with embryonic or fetal cardiac activity found on subsequent ultrasound studies. They demonstrated that slightly more than 10 % of patients with an IUP ultimately diagnosed had an initial hCG ≥ 1500 mIU/mL (5.9 % with levels of 1500–1999 mIU/mL; 4.5 % > 2000 mIU/mL) (Table 16.1). Connolly et al. performed a similar study including patients who had a TVS and hCG within 6 h of each other. They tabulated the levels associated with 99 % of IUPs. In this study, the discriminatory level was 3510 mIU/mL (Table 16.2). The current recommendation with an inconclusive ultrasound, assuming the patient is hemodynamically stable, is to follow the patient until the hCG level is at least 3000–3500 mIU/mL before declaring that an IUP is not visualized. This would defer medical intervention, such as methotrexate, until the diagnosis is clarified. This recommendation will largely avoid the inadvertent treatment of an IUP with methotrexate, with resultant fetal anomalies or fetal loss [13]. These hCG levels and recommendations pertain only to singleton pregnancies. Multiple gestations often have much higher hCG levels before identifying the intrauterine gestations. Thus, caution is advised in patients who have undergone assisted reproduction.

Table 16.1

Evidence against the hCG discriminatory level [12]

hCG (mIU/mL)

# (202)

%

Third–Fourth international standard

<1000

162

80.2

1000–1499

19

9.4

1500–1999

12

5.9

≥2000

9

4.5

Table 16.2

Reevaluation of the threshold and discriminatory levels [11]

hCG (mIU/mL)

Gestational Sac

Yolk Sac

Embryo

Threshold level

 390

1094

1394

Discriminatory level

3510

17,716

47,685

Endometrial Findings in Ectopic Pregnancy

Endometrial Thickness

When a gestational sac or yolk sac are not visualized, endometrial thickness may be helpful in assessing the location of a pregnancy. Spandorfer and Barnhart reviewed the ultrasound measured endometrial thickness in patients with a hCG below the discriminatory level. In general, an IUP had a mean endometrial thickness that was greater than an EP or a spontaneous miscarriage (13.42 mm vs. 5.95 mm vs. 9.28 mm, respectively) [14]. In their study, an endometrial thickness ≤ 8 mm was associated with an abnormal pregnancy in 97 % of cases. Thus, when evaluating early pregnancy, a thicker endometrium may be more commonly associated with an IUP, while a thinner endometrium is more common with an EP (Figs. 16.1 and 16.2).

A328333_1_En_16_Fig1_HTML.jpg

Fig. 16.1

Thicker endometrium (17.84 mm) in an early intrauterine pregnancy

A328333_1_En_16_Fig2_HTML.jpg

Fig. 16.2

Thin endometrium (3.3 mm) associated with an ectopic pregnancy

Intrauterine Fluid

The characteristics and shape of the intrauterine fluid in early pregnancy helps determine a pregnancy’s location. Benson et al. determined that no intrauterine fluid was present in 83.4 % of patients with an EP (191 of 229) [15]. Furthermore, 86.8 % of those patients with an EP and intrauterine fluid (33 of 38), also had an adnexal mass. In most of these patients (31 of 38, or 81.6 %), the fluid that was present tended to follow the contour of the endometrial cavity (Fig. 16.3). A smaller number (7 of 38, or 18.4 %) had a smooth walled cyst-like structure within the uterus. Such a cystic fluid collection can mimic an IUP. The differentiation is that the gestational sac of an IUP burrows into the decidua and is located slightly eccentrically (Fig. 16.4). One of the most important findings of this study was that a smooth-walled anechoic intrauterine cystic structure with no identified adnexal mass is associated with an IUP in 99.8 % of patients (Fig. 16.5).

A328333_1_En_16_Fig3_HTML.jpg

Fig. 16.3

Intrauterine fluid with low-level echoes following the endometrial contour in patient with an ectopic pregnancy

A328333_1_En_16_Fig4_HTML.jpg

Fig. 16.4

Gestational sac located in the posterior endometrium in an early intrauterine pregnancy

A328333_1_En_16_Fig5_HTML.jpg

Fig. 16.5

Smooth-walled anechoic sac in a patient with an early IUP

Adnexal Findings in Ectopic Pregnancy

In 1994, Brown and Doubilet reviewed ten studies with over 2000 patients with suspected EP to determine the adnexal findings associated with an ectopic pregnancy [16]. All ectopic pregnancies were surgically confirmed. They determined the following four categories of adnexal findings associated with ectopic pregnancies:

1.

2.

3.

4.

The first two findings are diagnostic of an EP. The tubal ring is associated with an ectopic pregnancy in 95 % of cases. Any complex or solid adnexal mass that is not intraovarian is associated with an ectopic pregnancy in 92 % of cases (Table 16.3). Such adnexal findings are present in almost 95 % of EP with each finding being visualized in 7.4 %, 8.3 %, 24.7 %, and 54.1 % (respectively) of EP [17].

Table 16.3

Adnexal criteria for ectopic pregnancy [1617]

Adnexal finding on TVS

Likelihood of ectopic (%) [16]

Frequency of findings [17]

Extrauterine embryo with cardiac activity

100

7.4

Adnexal mass with yolk sac without embryonic cardiac activity

100

8.3

Adnexal mass with central anechoic area and hyperechoic rim (“tubal ring”)

95

24.7

Any complex or solid adnexal mass other than a simple cyst or intraovarian lesion

92

54.1

Work-Up for Ectopic Pregnancy

This chapter reviews the hCG and ultrasound findings in ectopic pregnancy. The order in which one performs various tests, including serum progesterone, in patients with suspected EP was evaluated by Garcia and Barnhart in a 2001 paper [18]. The order of these tests included the following:

·               Ultrasound followed by quantitative hCG if the ultrasound findings were inconclusive

·               Quantitative hCG followed by ultrasound, when the hCG was >threshold value

·               Progesterone followed by ultrasound and, if inconclusive, then quantitative hCG

·               Progesterone followed by quantitative hCG and, when >threshold value, then ultrasound

·               Ultrasound followed by repeat ultrasound

·               Clinical examination only

They applied these algorithms to a theoretical cohort of 10,000 patients determining the number of ultrasounds, blood draws, dilatation and curettages, and laparoscopies performed. They then predicted the costs of the various strategies, and their effectiveness in diagnosing Eps. (Table 16.4). Ultimately they recommended either of the first two strategies, as the progesterone methods missed more ectopic pregnancies, the ultrasound only strategy was too costly, and the clinical exam only method to ineffective. Of note, although serum progesterone may be helpful in predicting viability of a pregnancy [19], the Garcia study confirmed the findings of others that progesterone lacks adequate sensitivity in distinguishing ectopic and intrauterine pregnancies [2022].

Table 16.4

Six strategies for diagnosing ectopic pregnancy [18]

Strategy

Days to Dx

Blood draws/10,000

Total charge per patient

Missed EP per 10,000

Interrupted IUP per 10,000

Ultrasound → hCG

1.46

5227

$1958

0

70

hCG → Ultrasound

1.66

14,375

$1842

0

122

P → Ultrasound → hCG

1.25

12,108

$1692

24

25

P → hCG → Ultrasound

1.26

15,003

$1569

24

39

Ultrasound → Ultrasound

1.21

0

$2486

0

121

Clinical exam only

1.0

0

$0

940

0

An Argument for Ultrasound First, Tubal Rupture Below the Threshold Level

The Connolly study previously discussed determined the threshold level of hCG should be lowered to 390 mIU/mL [11]. Prior to this study, many practitioners deferred ultrasound until the hCG level was ≥ 1000 mIU/mL. However, an early study by Saxon et al. demonstrated that 50 % of ruptured EPs had a hCG ≤ 999 mIU/mL [23]. This finding was confirmed by the 2014 report of Frates et al. also demonstrating that half of ruptured EPs had a hCG < 1000 mIU/mL. Thus, in patients with suspected EP, with bleeding, pain, and a positive qualitative pregnancy test, performing ultrasound first has value in identifying a definite IUP, EP, or a significant hemoperitoneum (Fig. 16.10). Not visualizing a significant hemoperitoneum allows a more conservative evaluation of such patients, while assuring patient safety.

A328333_1_En_16_Fig10_HTML.jpg

Fig. 16.10

“Tubal ring” consistent with an ectopic pregnancy in a patient with a hCG = 78 mIU/mL

Spontaneous Resolution of Pregnancy

The use of ultrasound for initial patient evaluation can result in identifying adnexal masses that are highly suggestive of an EP, in association with hCG levels that are below the threshold level (Fig. 16.11). Clinicians often feel obligated to treat patients for fear of rupture of an EP. Frates et al. determined that, regardless of the four adnexal findings noted in the prior section, there was no significant difference in rate of tubal rupture, which ranged from 17.6 to 28.4 % [17]. They found the most sensitive ultrasound finding of rupture was a moderate to large amount of free fluid. Thus, in a hemodynamically stable patient, there is no need for urgent intervention if there is either no or only a small amount of fluid in the cul-de-sac or abdomen. Korhonen et al. observed patients who had decreasing or stable hCG levels, an adnexal mass less than 4 cm in size, and no embryonic cardiac activity [24]. They found the rate of spontaneous resolution of a suspected or definite EP was 88 % when the initial hCG was less than 200 mIU/mL, and 25 % when the initial hCG was over 2000 mIU/mL. It must be emphasized that the hCG levels were stable or decreasing in these patients. However, this study demonstrated that observation is a reasonable option in well-selected patients, meeting criteria for spontaneous resolution of their EP.

A328333_1_En_16_Fig11_HTML.jpg

Fig. 16.11

Significant hemoperitoneum identified in a patient with a hCG = 465 mIU/mL

Unusual Ectopic Pregnancies

Heterotopic Pregnancy

The presence of an EP in combination with an IUP is designated a heterotopic pregnancy (Fig. 16.12). The rate of such pregnancies with spontaneous conception may be as low as 1 in 30,000. However, the increased use of assisted reproductive technology has led to an increased incidence of heterotopic pregnancy, perhaps as high as 1 in 110 [2526]. One must establish a routine of performing a thorough evaluation of all patients to avoid missing a concomitant EP when a definite IUP is identified.

A328333_1_En_16_Fig12_HTML.jpg

Fig. 16.12

Heterotopic pregnancy with both an intrauterine pregnancy and a tubal pregnancy

Interstitial Pregnancy

Interstitial pregnancies are those pregnancies located within the interstitial portion of the fallopian tube and lateral to the endometrial cavity (Fig. 16.13). Three-dimensional (3D) multiplaner reconstruction is incredibly valuable in localizing such pregnancies in the coronal plane. These pregnancies are defined by the ultrasound findings of an empty uterine cavity, a chorionic sac >1 cm from the lateral edge of the uterine cavity (the endometrium), with a thin (<5 mm) layer of myometrium surrounding the chorionic sac [27]. Such pregnancies have also been erroneously called cornual pregnancies. Technically, a cornual pregnancy refers to the implantation of an IUP in one of the cornua of a bicornuate, septate, or subseptate uterus [28]. Angular pregnancies refer to eccentric implantation of an IUP in the cornual area of a normally shaped uterus. Specific criteria for diagnosing an angular pregnancy were offered by Jansen and Elliott in 1981 [29]. These include the following:

A328333_1_En_16_Fig13_HTML.jpg

Fig. 16.13

Interstitial pregnancy identified on the 3D coronal view

·               Painful asymmetric uterine enlargement, followed by abortion or vaginal delivery

·               Directly observed lateral distension of the uterus, with or without rupture, accompanied by displacement of the round ligament reflection laterally;

·               Retention of the placenta in the uterine angle.

Angular pregnancies may carry to term, or at least viability, with more conservative management options available. In general, for all of these eccentrically located pregnancies, TVS, particularly 3D with its coronal views, has remarkably changed and clarified their diagnosis. 3D offers the ability to detect uterine anomalies and define the specific implantation site of a pregnancy. Thus, diagnostic criteria are now based on ultrasound rather than surgical pathology. Correct designation is imperative for proper communication of the ultrasound findings.

Ovarian Pregnancy

Ovarian pregnancies are rare with 0.15–3 % of EP occurring in the ovary [3031]. The diagnosis includes an empty uterine cavity with a gestational sac, yolk sac, fetal cardiac activity, or embryo visualized in the ovary [32] (Fig. 16.14). The ultrasound criteria for diagnosing an ovarian EP are (1) a wide echogenic ring with an internal echolucent area and (2) a yolk sac or fetal heart motion in the ovary [32]. The diagnosis is confirmed histologically by the Spiegelberg criteria which follow [33]:

A328333_1_En_16_Fig14_HTML.jpg

Fig. 16.14

Ovarian pregnancy with nonviable embryo identified in a gestational sac within the ovary

·               The gestation occupies a normal position of the ovary,

·               The gestational sac, thus the ovary, must be attached to the uterus by the ovarian ligament,

·               Ovarian tissue is histologically proven in the wall of the gestational sac, and

·               The fallopian tube on the affected side must be intact.

Abdominal Pregnancy

Abdominal pregnancies are quite rare. However, there is significant maternal and perinatal mortality and morbidity encountered with such pregnancies. This is due to implantation that occurs outside of the uterus, anywhere in the abdomen. Mortality is markedly higher when attachment occurs to the liver or spleen [34]. The diagnosis is often made later in pregnancy, as the pregnancy has the ability to expand in the abdomen. Studdiford’s criteria for appropriate diagnosis include the following [35]:

·               The fallopian tubes and ovaries are normal,

·               There is no abnormal connection, e.g., fistula, between the uterus and the abdominal cavity, and

·               The pregnancy is related solely to the peritoneal surface without sings of prior tubal rupture.

Diagnosis requires demonstration of an empty uterus, often normal in appearance, with the fetus contained within a gestational sac that is separate from the uterus and cervix [36] (Fig. 16.15).

A328333_1_En_16_Fig15_HTML.jpg

Fig. 16.15

Abdominal pregnancy on transabdominal ultrasound. Note the “empty” uterus

Cervical Pregnancy

Cervical pregnancy has an incidence of 1:1000–1:16,000 [37]. Diagnosis requires the demonstration of a gestational sac with a yolk sac or embryo in the endocervix, with an “empty” uterine cavity (Fig. 16.16). If the pregnancy implants higher, near the uterine cavity, it is called a cervico-isthmic pregnancy [38]. Previously, diagnosis of a cervical pregnancy was confirmed histologically with Rubin’s criteria applied to the surgical specimen. These criteria include [39]:

A328333_1_En_16_Fig16_HTML.jpg

Fig. 16.16

(ab) Cervical pregnancy with an embryo visualized in the endocervix

·               Cervical glands are opposite the trophoblastic tissue,

·               The trophoblastic attachment is below the entrance of the uterine vessels to the uterus or the anterior peritoneal reflection, and

·               Fetal elements are absent from the uterine corpus.

Current treatment is more conservative often with direct injection of methotrexate or potassium chloride (KCl), uterine artery embolization, or more conservative surgical approaches [37]. Thus, Rubin’s criteria cannot be applied to pregnancies treated without hysterectomy.

Cesarean Scar Pregnancies

These pregnancies are increasing in frequency. Timor-Tritsch and Monteagudo published an extensive literature review in 2012 regarding this topic [40], which will be reviewed in a subsequent chapter (see Chap. 17).

Summary

Ectopic pregnancy remains a challenging and critical diagnosis, as conservative medical and surgical treatment options rely on early diagnosis. Ultrasound remains the mainstay in diagnosis in coordination with other laboratory tests, particularly quantitative hCG and, in select patients, serum progesterone. Clinical care algorithms are appropriate when ultrasound fails to determine the pregnancy location, the so-called pregnancy of unknown location. In hemodynamically stable patients, such algorithms allow appropriate follow-up until one determines the pregnancy location and its viability status. An established examination protocol is crucial in evaluating patients with suspected ectopic pregnancy, to assure proper diagnosis of pregnancies that are implanted in unusual locations. Strict adherence to such protocols and algorithms allows timely and accurate diagnosis, with appropriate and patient specific treatment options.

Teaching Points

·               Patients with pregnancies of unknown location who are hemodynamically stable can be managed expectantly as most are ultimately diagnosed as a viable or failed intrauterine pregnancy.

·               A thin endometrium, ≤8 mm, is associated with an abnormal pregnancy in 97 % of patients whose hCG is below the discriminatory level.

·               In early pregnancy, a cystic structure within the endometrium, in the absence of an adnexal mass is associated with an intrauterine pregnancy in >99 % of patients.

·               A yolk sac or embryo with or without a heartbeat in the adnexa is diagnostic of an ectopic pregnancy

·               Ultrasound can be justified prior to obtaining a quantitative hCG, as 50 % of ruptured ectopic pregnancies have hCG levels <1000 mIU/mL.

·               Observation is appropriate in hemodynamically stable patients, as spontaneous resolution of ectopic pregnancy occurs in 25–88 % of patients.

·               There are specific criteria for diagnosis of ectopic pregnancies in unusual locations.

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