Ectopic pregnancy: Clinical manifestations and diagnosis

INTRODUCTION — An ectopic pregnancy is an extrauterine pregnancy. While the majority of ectopic pregnancies occur in the fallopian tube, nontubal sites include cervical, interstitial, ovarian, and abdominal pregnancy. Other abnormally implanted pregnancies, including hysterotomy (ie, cesarean, myomectomy) scar pregnancies can also occur. In rare cases, a multiple gestation may be heterotopic (include both an intrauterine and extrauterine pregnancy). Rupture of an ectopic pregnancy can result in life-threatening hemorrhage.

The clinical manifestations and diagnosis of ectopic pregnancy are reviewed here with a focus on tubal pregnancy. Medical and surgical treatment of ectopic pregnancy are reviewed elsewhere. 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")

●Management with methotrexate (see "Ectopic pregnancy: Methotrexate therapy")

●Surgical treatment (see "Tubal ectopic pregnancy: Surgical treatment")

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

●Diagnosis and management of uncommon ectopic or abnormally implanted pregnancy sites (see "Abdominal pregnancy" and "Cesarean scar pregnancy")

●Patients with pregnancy of unknown location (see "Approach to the patient with pregnancy of unknown location")

CLINICAL PRESENTATION

Overview — The most common clinical presentation of ectopic pregnancy is first-trimester vaginal bleeding and/or abdominal pain [1]. Ectopic pregnancy may also be asymptomatic. Clinicians should consider ectopic pregnancy as a diagnosis in any patient of reproductive age with vaginal bleeding and/or abdominal pain who has the following characteristics:

●Pregnant but does not have a confirmed intrauterine pregnancy.

●Pregnant and conceived with in vitro fertilization. (See 'Heterotopic pregnancy' below.)

●Pregnancy status uncertain, particularly if amenorrhea of >4 weeks preceded the current vaginal bleeding.

●In rare cases, a patient who presents with hemodynamic instability and an acute abdomen that is not explained by another diagnosis.

Clinical manifestations of ectopic pregnancy typically appear six to eight weeks after the last normal menstrual period but may occur later, especially if the pregnancy is at an extrauterine site other than the fallopian tube. Normal pregnancy discomforts (eg, breast tenderness, frequent urination, nausea) are sometimes present. Early pregnancy symptoms may be less common in patients with ectopic pregnancy because progesterone, estradiol, and human chorionic gonadotropin levels may be lower than in normal pregnancy [2,3].

An ectopic pregnancy may be unruptured or ruptured at the time of presentation to medical care. Tubal rupture (or rupture of other structures in which an ectopic pregnancy is implanted) can result in life-threatening intraabdominal hemorrhage. Rupture may present with severe or persistent abdominal pain or symptoms suggestive of ongoing blood loss (eg, feeling faint or loss of consciousness).

The following large studies are examples of the frequency of findings in ectopic pregnancy:

●In a retrospective study of 2026 pregnant patients who presented to the emergency department with first-trimester vaginal bleeding and/or abdominal pain, 376 (18 percent) were diagnosed with ectopic pregnancy [4]. Of these 376 patients, 76 percent had vaginal bleeding and 66 percent had abdominal pain.

●In a population-based registry of ectopic pregnancy from France, the incidence of rupture was 18 percent [5].

Vaginal bleeding — The volume and pattern of vaginal bleeding vary, and there is no bleeding pattern that is pathognomonic for ectopic pregnancy. Bleeding may range from scant brown staining to hemorrhage. Bleeding is usually intermittent but may occur as a single episode or continuously.

The vaginal bleeding associated with ectopic pregnancy is typically preceded by amenorrhea [6]. However, some patients may misinterpret bleeding as normal menses and may not realize they are pregnant prior to developing symptoms associated with ectopic pregnancy. This is particularly true in patients who have irregular menses or who do not keep track of menstrual cycles. The presumptive source of such bleeding is sloughing of the decidualized endometrium rather than bleeding from the tube itself.

Bleeding occurs in many other conditions in early pregnancy. (See 'Differential diagnosis' below.)

Abdominal pain — The timing, character, and severity of abdominal pain vary, and there is no pain pattern that is pathognomonic for ectopic pregnancy.

Pain is usually located in the pelvis and may be diffuse or localized to one side. Pain tends to present between five and seven weeks of gestation as the tube becomes sufficiently distended. Patients may describe their pain as continuous or intermittent, dull or sharp, or mild or severe. Tubal rupture may be associated with an abrupt onset of severe pain. In cases in which there is intraperitoneal blood that reaches the upper abdomen or in rare cases of abdominal pregnancy, the pain may be in the middle or upper abdomen. If there is sufficient intraabdominal bleeding to reach the diaphragm, referred pain may be felt in the shoulder. Blood pooling in the posterior cul-de-sac (pouch of Douglas) may cause an urge to defecate.

Abdominal pain occurs in many other conditions in early pregnancy. (See 'Differential diagnosis' below.)

DIAGNOSIS

●The diagnosis of ectopic pregnancy should be suspected in a pregnant patient with no evidence of an intrauterine pregnancy on transvaginal ultrasound (TVUS) and any of the following:

•Visualization of a complex inhomogenous extraovarian adnexal mass, an extraovarian adnexal mass containing an empty gestational sac, or intraperitoneal bleeding on TVUS. (See 'Transvaginal ultrasound' below.)

•A serum human chorionic gonadotropin (hCG) that is rising abnormally. In our practice, we generally define an abnormal rise as <35 percent over two days. Historically, this number was <50 percent over two days; however, this was based on a limited number of patients [7]. For patients in whom an initial hCG level is <10,000 mIU/mL, the actual expected rate of rise over 48 hours is dependent on initial hCG level; the expected rate of increase is 49 percent for an initial hCG level of <1500 mIU/mL, 40 percent for an initial hCG level of 1500 to 3000 mIU/mL, and 33 percent for an initial hCG level of >3000 to <10,000 mIU/mL [8]. This is described in more detail separately. (See "Approach to the patient with pregnancy of unknown location", section on 'hCG testing'.)

•Abdominal pain and/or vaginal bleeding, especially in those patients with risk factors for ectopic pregnancy (table 1). (See 'Step one: History and physical examination' below.)

●The diagnosis of ectopic pregnancy can be confirmed when any of the following are present:

•Visualization of an extrauterine gestational sac with a yolk sac or embryo (with or without a heartbeat) on TVUS. (See 'Transvaginal ultrasound' below.)

•A positive serum hCG and no products of conception on uterine aspiration with subsequent rising or plateauing hCG levels. (See 'Ancillary diagnostic tests' below.)

•Visualization at surgery with histologic confirmation following resection of ectopic pregnancy tissue. (See 'Surgical management' below.)

DIFFERENTIAL DIAGNOSIS — The classic findings of ectopic pregnancy are vaginal bleeding and/or abdominal pain in the setting of a positive pregnancy test.

The differential diagnosis of bleeding with or without pain early in pregnancy also includes [9]:

●Physiologic (eg, implantation bleeding)

●Spontaneous abortion

●Cervical, vaginal, or uterine pathology (eg, cervical polyp)

●Subchorionic hematoma

●Gestational trophoblastic disease (human chorionic gonadotropin concentration is unusually high for the gestational age)

Even if a cervical or vaginal source of bleeding is identified, all patients with first-trimester bleeding should be evaluated by transvaginal ultrasound. The evaluation of first-trimester vaginal bleeding is discussed separately. (See "Evaluation and differential diagnosis of vaginal bleeding before 20 weeks of gestation" and "Pregnancy loss (miscarriage): Terminology, risk factors, and etiology" and "Causes of female genital tract bleeding" and "Hydatidiform mole: Epidemiology, clinical features, and diagnosis".)

The differential diagnosis of lower abdominal pain in pregnant patients includes urinary tract infection, kidney stones, diverticulitis, appendicitis, ovarian neoplasms, ovarian cyst rupture, large size or hemorrhage into an ovarian cyst, ovarian torsion, leiomyomas, and round ligament pain. These disorders are not typically accompanied by vaginal bleeding. (See "Evaluation of the adult with abdominal pain".)

DIAGNOSTIC EVALUATION

Overview — Any pregnant patient with vaginal bleeding and/or abdominal pain should be evaluated for ectopic pregnancy. The main goals and steps of the evaluation are to:

●Confirm that the patient is pregnant.

●Evaluate the patient for hemodynamic instability since rupture of the structure in which the ectopic pregnancy is implanted typically causes hemorrhage. Failure to diagnose ectopic pregnancy before tubal rupture increases maternal morbidity and mortality and limits treatment options.

●Determine the site of the pregnancy (ie, whether an intrauterine pregnancy [IUP] or ectopic pregnancy). In rare cases, the pregnancy is heterotopic. In the absence of definitive evidence of an IUP or ectopic pregnancy on ultrasound, it is sometimes impossible to differentiate between an early IUP, an ectopic pregnancy, and an early failed IUP. These pregnancies are referred to as a pregnancy of unknown location. (See "Approach to the patient with pregnancy of unknown location".)

Hemodynamically unstable patients — Patients with ectopic pregnancy may become hemodynamically unstable if there is a rupture of, and hemorrhage from, the structure in which the pregnancy is implanted, usually the fallopian tube [10]. However, in young healthy patients, vital signs, including postural changes, may be normal early in the course of significant bleeding due to compensatory mechanisms [11].

Rupture should be suspected in patients with a sudden onset of severe and persistent abdominal or pelvic pain, or symptoms or signs suggestive of hemodynamic compromise (eg, feeling faint, hypotension, tachycardia). The typical findings of rupture are abdominal or pelvic pain, shoulder pain due to diaphragmatic irritation by blood in the peritoneal cavity, and, eventually, hypotension and shock.

Physical examination is often unremarkable or may reveal lower abdominal tenderness. If rupture with significant bleeding has occurred, the abdomen may be distended and the patient may have diffuse, localized, and/or rebound tenderness.

If rupture is suspected, the patient should be transferred to a center where resuscitation and immediate surgical treatment can be provided. A complete pelvic examination in the emergency department is not always possible and may be deferred until the patient is in the operating room. The pelvic examination and expected findings are described below. (See 'Step one: History and physical examination' below.)

Laboratory testing includes a complete blood count, serum hCG level, Rh blood type, and crossmatching. (See 'Human chorionic gonadotropin' below and 'Other testing' below.)

Role of focused transabdominal ultrasound — An abdominal ultrasound can be used to quickly assess for intraperitoneal hemorrhage. In the absence of abdominal trauma, identification of intraperitoneal bleeding in a patient of reproductive age should be considered a potential ruptured ectopic pregnancy until proven otherwise. A hemodynamically unstable patient with this finding should undergo urgent surgical consultation and exploration.

If intraperitoneal hemorrhage is not found on focused abdominal ultrasound, a ruptured ectopic pregnancy is unlikely to be the cause of the patient's hemodynamic instability.

If heavy vaginal bleeding is present and is thought to be the cause of the hypovolemia, the patient may require emergency surgical management with uterine aspiration for a suspected incomplete abortion. If neither hemoperitoneum nor heavy vaginal bleeding is present, further evaluation for other causes of hypotension and shock is required. (See "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock".)

Surgical management — Ruptured ectopic pregnancy is managed surgically. (See "Tubal ectopic pregnancy: Surgical treatment".)

Hemodynamically stable patients

Step one: History and physical examination

●History – A menstrual history is taken to estimate the gestational age (calculator 1). However, it is important to note that gestational age as calculated by last menstrual period may be inaccurate, and ultrasound is often required to obtain correct dating.

Risk factors for ectopic pregnancy should be elicited, including prior ectopic pregnancy, prior tubal pathology or surgery (eg, pelvic inflammatory disease or tubal ligation), current use of an intrauterine device, and in vitro fertilization (IVF) (table 1). However, over 50 percent of patients do not have an identifiable risk factor for ectopic pregnancy [12]. (See "Ectopic pregnancy: Epidemiology, risk factors, and anatomic sites", section on 'Risk factors'.)

Medical comorbidities that are contraindications to methotrexate therapy (eg, renal or hepatic disease) should be identified as these may affect treatment options. (See "Ectopic pregnancy: Choosing a treatment", section on 'Choosing between methotrexate and surgery'.)

●Physical examination – Hemodynamic stability is assessed, and a complete pelvic examination is performed. Speculum examination is used to assess the volume of bleeding by noting the quantity of blood in the vagina and presence or absence of active bleeding passing through the external os of the cervix.

On bimanual pelvic examination, the adnexa should be palpated gently since excessive pressure may rupture an ectopic pregnancy. Cervical motion, adnexal, and/or abdominal tenderness may be present, and an adnexal mass can be detected in some patients; however, this examination is often unremarkable in a patient with a small, unruptured ectopic pregnancy. The uterus may be somewhat enlarged but will likely be smaller than appropriate for gestational age. Uterine enlargement in patients with ectopic pregnancy may be due to endocrine changes of pregnancy, rare cases of heterotopic pregnancy, or incidental uterine pathology (most commonly, uterine fibroids).

Step two: Initial ultrasound and hCG

Transvaginal ultrasound — Transvaginal ultrasound (TVUS) is the most useful imaging test for determining the location of a pregnancy. TVUS should be performed at the time of presentation of a suspected ectopic pregnancy and may need to be repeated, depending on the findings, the hCG level, or subsequent suspicion of rupture. The ultrasound should be performed by a clinician with expertise in gynecologic ultrasound whenever possible.

TVUS alone can:

●Diagnose an IUP

•Findings diagnostic of an IUP include a gestational sac with a yolk sac or embryo (with or without a heartbeat) in the uterus. Rarely, an interstitial pregnancy or rudimentary horn pregnancy is misdiagnosed as an IUP, or a heterotopic pregnancy is misdiagnosed as an IUP alone. (See 'Heterotopic pregnancy' below and 'Interstitial pregnancy' below.)

A gestational sac alone (without a yolk sac or embryo) is not sufficient for diagnosis, but highly suggestive of an early IUP. (See "Ultrasonography of pregnancy of unknown location", section on 'Pseudosac'.)

●Diagnose an ectopic pregnancy

•The most specific signs of an ectopic pregnancy include a gestational sac with a yolk sac or embryo (with or without a heartbeat) outside of the uterus [13].

As above, a gestational sac alone (without a yolk sac or embryo) is insufficient for diagnosis.

The reported sensitivity and specificity of TVUS for the detection of an ectopic pregnancy at a serum hCG of >2000 mIU/mL are 10.9 and 95.2 percent, respectively [14].

●Detect findings that are suggestive, but not diagnostic, of ectopic pregnancy. These findings include [13]:

•A complex inhomogenous extraovarian adnexal mass. This is the most common ultrasound finding in ectopic pregnancy and is present in 89 percent or more of cases [15,16].

•An extraovarian adnexal mass containing an empty gestational sac (sometimes referred to as a "tubal ring").

●Detect findings suggestive of ectopic rupture

•A finding of fluid with debris (consistent with blood) in the pelvic cul-de-sac and/or abdomen may be consistent with rupture of an ectopic pregnancy. Blood clot may also surround the uterus and adnexa on the side of the patient's pain.

However, fluid debris is a nonspecific finding; a small amount of fluid is often visualized in healthy patients and also may be present in other conditions, such as a ruptured ovarian cyst.

If TVUS is nondiagnostic, it may be because the gestation is too early to be visualized on ultrasound. If so, the patient has a pregnancy of unknown location. Evaluation of such patients is discussed in detail separately. (See "Approach to the patient with pregnancy of unknown location", section on 'Initial evaluation' and "Approach to the patient with pregnancy of unknown location", section on 'Subsequent testing in selected patients'.)

The details of performing an ultrasound evaluation for ectopic pregnancy versus IUP are also presented separately. (See "Ultrasonography of pregnancy of unknown location".)

Human chorionic gonadotropin — Serum, rather than urine, hCG is the preferred test for a pregnant patient with pain and/or bleeding. It is not possible to determine whether a pregnancy is normal from a single hCG level because there is a wide range of normal levels at each week of pregnancy [17]. (See 'Step three: Follow-up testing for selected patients' below.)

In pregnant patients, hCG can be detected in serum as early as six days after the luteinizing hormone surge (approximately 21 to 22 days after the first day of the last menstrual period in patients with 28-day cycles). (Related Lab Interpretation Monograph(s): "Positive hCG in women", section on 'Pregnancy'.)

The hCG concentration in a normal IUP rises in a curvilinear fashion until approximately 41 days of gestation, after which it rises more slowly until approximately 10 weeks, and then declines until reaching a plateau in the second and third trimesters [18]. (See "Clinical manifestations and diagnosis of early pregnancy", section on 'Serum pregnancy test'.)

hCG discriminatory zone — The discriminatory zone is the serum hCG level above which a gestational sac should be visualized when an IUP is present. It is important to emphasize that a patient should not be diagnosed or treated for an ectopic pregnancy based on a single serum hCG level.

For TVUS, we use a discriminatory zone of 3510 mIU/mL. However, results and discriminatory zone vary by laboratory and institution, and some institutions set the discriminatory zone at 2000 mIU/mL [19].

Setting the discriminatory zone at 3510 mIU/mL increases the ability to diagnose a live IUP on TVUS, if present, but also increases the risk of delaying a diagnosis of an ectopic pregnancy. In a study of 651 patients with first-trimester bleeding or pain, among live IUPs, a gestational sac was seen at differing hCG levels in the following proportion of pregnancies: 1500 mIU/mL (80 percent had a gestational sac visualized), 2000 mIU/mL (91 percent), and 3510 mIU/mL (99 percent) [19]; 1 percent of IUPs will not be visualized on TVUS when the discriminatory zone is set at 3510 mIU/mL.

It is important to note that there is a variation in the level of hCG across pregnancies for each gestational age, and the discriminatory levels are not always reliable and thus should be used with caution. In addition, other factors can affect the early detection of a gestational sac, including the skill of the ultrasonographer, the quality of the ultrasound equipment, and the presence of physical factors (eg, fibroids, multiple gestation, large body habitus).

Other testing

Rh typing — Rh blood typing with administration of anti-D immune globulin in Rh-negative (D-negative) patients is discussed in detail separately. (See "RhD alloimmunization: Prevention in pregnant and postpartum patients", section on 'Guidelines for prevention of anti-D alloimmunization (United States)'.)

Pretreatment laboratory tests — Patients with a suspected ectopic pregnancy may require treatment with methotrexate. Although treatment decisions will be made later in the course of the evaluation, methotrexate pretreatment blood tests are typically ordered with the initial blood draw. In addition to a complete blood count, these also include renal and liver function tests. (See "Ectopic pregnancy: Methotrexate therapy", section on 'Pretreatment evaluation'.)

Ancillary diagnostic tests — Additional diagnostic tests (eg, serum progesterone, uterine aspiration) have been used in patients with suspected ectopic pregnancy. Except in selected cases, such tests do not provide additional clinically useful information.

●Serum progesterone – Serum progesterone concentrations are higher in viable IUPs than in ectopic pregnancies and IUPs that are destined to abort [20], and measurement of serum progesterone may be useful in a patient with abdominal pain and bleeding who has a serum hCG level below that expected for the gestational age. However, the definition of low progesterone is unclear, and in our experience, progesterone measurements merely confirm diagnostic impressions already obtained by hCG measurements and TVUS. Therefore, we do not routinely measure serum progesterone.

The limited role of serum progesterone in patients with pregnancy of unknown location or pregnancy loss is discussed in more detail separately. (See "Approach to the patient with pregnancy of unknown location", section on 'Laboratory testing' and "Pregnancy loss (miscarriage): Clinical presentations, diagnosis, and initial evaluation", section on 'Perform physical and laboratory examinations'.)

●Uterine aspiration – The intrauterine location of a pregnancy is diagnosed with certainty (except in the rare case of a heterotopic pregnancy) if trophoblastic tissue is obtained by uterine curettage. Of course, the use of curettage as a diagnostic tool is limited by the potential for disruption of a viable pregnancy. Knowing the results of aspiration avoids unnecessary methotrexate treatment of the 30 percent of patients without ectopic pregnancy.

A decision analysis comparing the cost/complication rates in patients who undergo diagnostic aspiration before administration of methotrexate with those who do not have aspiration concluded there was no significant benefit of one approach over the other [21]. However, the authors' preference was to perform aspiration in these patients to be more certain of the diagnosis, and they felt this information was useful prognostically (eg, risk of recurrence) and for future decision making.

By contrast, we and others believe it is more practical and less invasive to continue observation or administer one dose of methotrexate than to perform aspiration [22,23]. The side effects of one dose of methotrexate are negligible (in patients without contraindication to methotrexate). In addition, aspiration carries a risk of intrauterine adhesion formation. (See "Ectopic pregnancy: Methotrexate therapy" and "Intrauterine adhesions: Clinical manifestation and diagnosis".)

Step three: Follow-up testing for selected patients — For a hemodynamically stable patient in whom a diagnosis of ectopic pregnancy or IUP cannot be made based on the initial TVUS (ie, pregnancy of unknown location), follow-up is often with serial hCG and repeat ultrasound. (See "Approach to the patient with pregnancy of unknown location", section on 'Hemodynamically stable patients'.)

Probability calculators may also be used to help predict the risk of ectopic pregnancy in such patients. In one retrospective study evaluating 2185 pregnant patients at <13 weeks gestation who presented to the emergency department, an algorithm using a Bayesian model correctly identified 98.9 percent of patients as having or not having an ectopic pregnancy [24]. The algorithm failed to identify two patients who were subsequently diagnosed with ectopic pregnancy; the other 22 patients with a positive test were subsequently diagnosed with an IUP. Use of other mathematical models (eg, "M4," "M6-P") to help estimate risk of ectopic pregnancy are discussed in detail separately. (See "Approach to the patient with pregnancy of unknown location", section on 'Subsequent testing in selected patients'.)

By contrast, a patient with a pregnancy of unknown location in whom the pregnancy is undesired may be able to forgo follow-up testing and undergo expedited active management (eg, diagnostic uterine aspiration [with laparoscopy if an adnexal mass is present]). (See "Approach to the patient with pregnancy of unknown location", section on 'Hemodynamically stable patients'.)

NATURAL HISTORY — If left untreated, an ectopic pregnancy in the fallopian tube can progress to a tubal abortion or tubal rupture, or it may regress spontaneously.

●Tubal rupture – Tubal rupture is usually associated with profound hemorrhage, which can be fatal if surgery is not performed expeditiously to remove the ectopic gestation. Ruptured ectopic pregnancy is the major cause of pregnancy-related maternal mortality in the first trimester [25]. Most of these deaths occur prior to hospitalization or proximate to the patient's arrival in the emergency department.

●Tubal abortion – Tubal abortion refers to expulsion of the products of conception through the fimbria. This can be followed by resorption of the tissue or by reimplantation of the trophoblasts in the abdominal cavity (ie, abdominal pregnancy) or on the ovary (ie, ovarian pregnancy). Tubal abortion may be accompanied by severe intraabdominal bleeding, necessitating surgical intervention, or by minimal bleeding, which would not require further treatment.

●Spontaneous resolution – Spontaneous resolution of an ectopic pregnancy can occur, although it is difficult to predict which patients will experience uncomplicated spontaneous resolution. This is discussed in more detail separately. (See "Ectopic pregnancy: Expectant management of tubal pregnancy".)

In rare instances, gestational products left in the fallopian tube can cause tubal obstruction.

SPECIAL CONSIDERATIONS

Multiple gestation — Multiple gestation should always be considered in the differential diagnosis when the human chorionic gonadotropin (hCG) level is above the hCG discriminatory zone but an intrauterine pregnancy (IUP) cannot be visualized on transvaginal ultrasound (TVUS). (See 'hCG discriminatory zone' above.)

In patients with an intrauterine multiple pregnancy, the serum hCG level will be higher than anticipated for a singleton pregnancy, and yet, ultrasound examination may not reveal an IUP [26]. Levels of over 9000 mIU/mL have been described for intrauterine triplet pregnancies unobserved by TVUS [27].

Heterotopic pregnancy — The investigation for ectopic pregnancy can be terminated, under most circumstances, if a transvaginal sonogram reveals an IUP. Heterotopic pregnancy (combined IUP and extrauterine pregnancy) is rare, except among patients conceiving through assisted reproduction technology (ART). The extrauterine pregnancy is usually in the fallopian tube but can be at another location, such as the cervix. (See "Ectopic pregnancy: Epidemiology, risk factors, and anatomic sites", section on 'Anatomic sites'.)

●Clinical presentation – The clinical presentation of heterotopic intrauterine and tubal pregnancies closely mimics the symptoms of threatened abortion and isolated ectopic pregnancy. The uterus is enlarged consistent with gestational age and there may be abdominal pain, vaginal bleeding, and/or an adnexal mass. Rupture can result in acute abdomen and hemodynamic shock.

●Diagnosis – Early diagnosis of heterotopic pregnancy is difficult. These patients may not be diagnosed until they become symptomatic or have reached a more advanced gestational age (eg, 16 weeks [28]) because the possibility of an additional ectopic pregnancy is generally not considered when an intrauterine gestation is observed on ultrasound. Thus, a high index of suspicion for this diagnosis is important, especially in patients who have undergone ART and who experience abdominal pain or vaginal bleeding.

Serial hCG concentrations are not informative as they primarily reflect production from the intrauterine pregnancy.

On ultrasound examination, the sonographer should carefully examine not only the uterus but also the adnexa and interstitial portion of the fallopian tube, especially in patients who conceive following ART. The diagnosis is suggested by visualization of both an IUP and the presence of a complex adnexal mass, an extra-endometrial gestational sac (eg, interstitial pregnancy), or echogenic fluid in the posterior cul-de-sac. The diagnosis is confirmed when the adnexal mass or extra-endometrial sac contains a yolk sac or embryo/fetal pole [29,30]. (See 'Uncommon sites of ectopic pregnancy' below.)

The management of heterotopic pregnancy is discussed separately. (See "Ectopic pregnancy: Choosing a treatment", section on 'Heterotopic pregnancy'.)

Uncommon sites of ectopic pregnancy — Ectopic pregnancy may occur in a nontubal location or even bilaterally [31]. Nontubal sites include cervical, rudimentary uterine horn, interstitial, ovarian, and abdominal pregnancy. Regardless of the location, the endometrium often responds to ovarian and placental production of pregnancy-related hormones, so vaginal bleeding is a common symptom.

Ovarian pregnancy — The clinical presentation of ovarian pregnancy is similar to that of tubal ectopic pregnancy (ie, vaginal bleeding and/or abdominal pain). (See 'Clinical presentation' above.)

Sonographic differentiation between a hemorrhagic ovarian cyst or pregnancy in the distal fallopian tube can be difficult [32]. Ultrasound evaluation for ovarian pregnancy is discussed in detail separately. (See "Ultrasonography of pregnancy of unknown location".)

The diagnosis of ovarian pregnancy is typically made at the time of surgery. Strict histopathologic criteria are used to distinguish ovarian pregnancies from those originating in the fallopian tube. The exact diagnosis is not clinically important since these pregnancies are usually treated by surgical excision of the involved organs. Methotrexate treatment has been successful in case reports [33]. (See "Ectopic pregnancy: Epidemiology, risk factors, and anatomic sites", section on 'Ovarian pregnancy'.)

Interstitial pregnancy — The interstitial portion of the fallopian tube is the proximal segment that is embedded within the muscular wall of the uterus (figure 1). A pregnancy implanted at this site is called an interstitial pregnancy; the term "cornual pregnancy" is also widely used (but less preferred) to describe a pregnancy at this location. Originally, cornual pregnancy referred only to pregnancies implanted in either the horn of a bicornuate or didelphys uterus, a rudimentary horn of a unicornuate uterus, or in one side of a septated or partially septated uterus.

An interstitial pregnancy can be difficult to distinguish on ultrasound from an IUP that is eccentrically positioned (and sometimes referred to as angular pregnancy). The key finding is that an interstitial pregnancy is extra-endometrial. As interstitial pregnancies advance, ultrasound may show a bulge at the interstitial region without a communication to the endometrial cavity; typically there will be no myometrium surrounding a portion of the gestational sac. (See "Ultrasonography of pregnancy of unknown location".)

Grossly, an interstitial pregnancy appears as a gestational swelling lateral to the insertion of the round ligament. The unique anatomic location of an interstitial pregnancy often leads to a delay in diagnosis, although an average delay of only four days in comparison with tubal pregnancies was reported in a large series [34].

Since the interstitial portion of the fallopian tube can dilate more readily than other portions of the tube, pain usually presents later in gestation (between 8 and 10 weeks), with rupture occurring in approximately 20 to 50 percent of cases [35-37].

Although the maternal mortality rate associated with tubal pregnancy is decreasing, the rate for interstitial pregnancies remains at 2.0 to 2.5 percent because of misdiagnosis of these gestations as IUPs.

Other sites — Cervical and abdominal pregnancies are rare. Diagnosis and management of these pregnancies are discussed in detail separately. (See "Cervical pregnancy: Diagnosis and management" and "Abdominal pregnancy".)

Other abnormally implanted pregnancies, including hysterotomy (ie, cesarean, myomectomy) scar pregnancies are distinct from ectopic pregnancy in that they occur within the uterine cavity. (See "Cesarean scar pregnancy".)

Screening asymptomatic patients — Routine prenatal care does not include serial measurement of serum hCG or early TVUS. The exceptions to this are patients at high risk of an ectopic pregnancy, including those with an IVF pregnancy; pregnancy after reconstructive surgery of the fallopian tube; or prior history of ectopic pregnancy.

In our practice, we monitor patients at high risk of ectopic pregnancy (table 1) with serial serum hCG levels and TVUS. We use the same clinical protocol as for a hemodynamically stable patient with a pregnancy of unknown location and start with the first missed menses or after embryo transfer for IVF. The goal is to establish the diagnosis early to avoid rupture. (See "Approach to the patient with pregnancy of unknown location", section on 'Hemodynamically stable patients'.)

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" and "Society guideline links: Ultrasound imaging in 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 5^th to 6^th 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 10^th to 12^th 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

●Sites of ectopic pregnancy – An ectopic pregnancy is an extrauterine pregnancy. Almost all ectopic pregnancies occur in the fallopian tube, but other possible sites include cervical, interstitial, ovarian, or abdominal. Other abnormally implanted pregnancies, including hysterotomy (ie, cesarean, myomectomy) scar pregnancies, can also occur. In rare cases, a multiple gestation may be heterotopic (include both an intrauterine pregnancy [IUP] and an extrauterine pregnancy). (See 'Introduction' above and 'Uncommon sites of ectopic pregnancy' above.)

●Clinical presentation – Abdominal pain and/or vaginal bleeding are the most common symptoms of ectopic pregnancy. Ectopic pregnancy should be suspected in any patient of reproductive age with these symptoms, especially those who have risk factors for ectopic pregnancy (table 1). However, over 50 percent of patients are asymptomatic before tubal rupture and do not have an identifiable risk factor for ectopic pregnancy. (See 'Clinical presentation' above.)

●Diagnosis – In a pregnant patient with no IUP on transvaginal ultrasound (TVUS), the diagnosis of ectopic pregnancy is (see 'Diagnosis' above):

•Suspected when any of the following are present:

-An extraovarian adnexal mass or intraperitoneal bleeding on TVUS.

-An abnormally rising serum human chorionic gonadotropin (hCG) level.

-Abdominal pain and/or vaginal bleeding in a patient with risk factors for ectopic pregnancy.

•Confirmed when any of the following are present:

-An extrauterine gestational sac with a yolk sac or embryo on TVUS.

-No products of conception are identified on uterine aspiration (if performed).

-Ectopic pregnancy tissue is visualized at surgery with histologic confirmation following resection.

●Hemodynamically unstable patients – Patients with ectopic pregnancy may become hemodynamically unstable if there is a rupture of, and hemorrhage from, the structure in which the pregnancy is implanted, usually the fallopian tube. (See 'Hemodynamically unstable patients' above.)

•Rupture should be suspected in patients with a sudden onset of severe and persistent abdominal pain, symptoms of faintness, or vital signs suggestive of hemodynamic compromise (eg, hypotension, tachycardia). These patients should be evaluated immediately in an emergency department. (See 'Hemodynamically unstable patients' above.)

•A ruptured ectopic pregnancy is a clinical diagnosis made primarily based on a finding of echogenic fluid (consistent with blood) in the pelvic cul-de-sac (and typically also surrounding the uterus and adnexa on the side of the patient's pain) and/or abdomen on focused abdominal ultrasound combined with the presence of abdominal pain and/or tenderness. (See 'Role of focused transabdominal ultrasound' above.)

•If rupture is suspected, the patient should undergo emergency surgical management. (See 'Surgical management' above.)

●Hemodynamically stable patients – For hemodynamically stable patients with a suspected ectopic pregnancy, a complete history and physical examination are performed along with a serum hCG level and TVUS. (See 'Hemodynamically stable patients' above.)

•The discriminatory zone is the serum hCG level above which a gestational sac should almost always be visualized on ultrasound when an IUP is present. This level varies by laboratory and institution. For TVUS, we use a discriminatory zone of 3510 mIU/mL. However, a diagnosis of ectopic pregnancy cannot be made based on a single hCG result. (See 'hCG discriminatory zone' above.)

•Additional laboratory testing that may be performed includes a complete blood count to evaluate for anemia, RhD blood typing in case anti-D immune globulin is indicated, and renal and liver function tests in case methotrexate therapy is administered. (See 'Pretreatment laboratory tests' above.)

●Differential diagnosis – If an ectopic pregnancy has been ruled out, the patient should be evaluated for other causes of abdominal pain and/or vaginal bleeding in pregnancy (eg, spontaneous abortion, subchorionic hemorrhage, or nonobstetric causes, such as cervical polyp or other cervical pathology). (See 'Differential diagnosis' above.)