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eMedicine Specialties > Emergency Medicine > Obstetrics & Gynecology

Pregnancy, EctopicThomas J Chi, MD, Assistant Clinical Professor, Emergency Medicine, State University of New York Downstate MedicalCenter; Attending Physician, Emergency Medicine, Kings County Hospital Center, New York

Updated: Nov 9, 2009

Introduction

Background

An ectopic pregnancy is any implantation of a fertilized ovum at a site other than the

endometrial lining of the uterus. Virtually all ectopic pregnancies are considered nonviable and

are at risk of eventual rupture. Rupture of an ectopic pregnancy and resulting hemorrhage is

one of the leading causes of first-trimester maternal death in the developed world; therefore,

early diagnosis and treatment (before rupture) is important to prevent morbidity and mortality.

[1 ]

An endovaginal sonogram demonstrates an early ectopic pregnancy. An echogenic ring

(tubal ring) found outside of the uterus can be seen in this view.


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Pregnancy, ectopic. An endovaginal sonogram reveals an intrauterine pregnancy at

approximately 6 weeks. A yolk sac (ys), gestational sac (gs), and fetal pole (fp) are

depicted.

Pathophysiology

The faulty implantation that occurs in ectopic pregnancy occurs because of a defect in the

anatomy or normal function of either the fallopian tube (as in surgical or infectious scarring), the

ovary (as in women undergoing fertility treatments), or the uterus (as in cases of bicornuate

uterus, cesarean delivery scar).

Reflecting this, about 95% of ectopic pregnancies occur in the fallopian tube 70% in the

ampulla; 12%, isthmus; 11.1%, fimbria; and 2.4%, interstitium (or cornual region of the uterus).

Some ectopic pregnancies implant in the cervix (28 wk) andhave the potential for catastrophic rupture and bleeding.[4 ]

Frequency

United States

Using inpatient data derived from the National Hospital Discharge Survey, the Centers for

Disease Control and Prevention (CDC) reported that the incidence of ectopic pregnancies rose


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dramatically in the United States from 1970 until 1989, from 4.5 to 16.0 per 1,000 reported

pregnancies. [5 ]Since then, changes in the management of ectopic pregnancy have made it

difficult to reliably monitor incidence (and therefore mortality rates).[6 ]

A review of hospital discharges in California found a rate of 15 cases per 1,000 in 1991,

declining to a rate of 9.3 cases per 1,000 in 2000, [7 ]but a review of electronic medical records

(inpatient and outpatient) from a large health maintenance organization in northern California

found a stable rate of 20.7 cases per 1,000 reported pregnancies from 1997-2000.[8 ]This

suggests that the incidence of ectopic pregnancy in the United States remained steady at about

2% in the 1990s, despite the shift to outpatient treatment.

International

The increase in incidence of ectopic pregnancy in the 1970s in the United States was also

mirrored in Africa, although data there tend to be hospital-based rather than nationwide surveys,

with most recent estimates in the range of 1.1-4.6%. [9 ]

The United Kingdom estimates the incidence of ectopic pregnancy at about 11.1 per 1,000

reported pregnancies from 1997-2005 compared with 9.6 per 1,000 from 1991-1993. [10 ]

Mortality/Morbidity

From 1970-1989, the US mortality rate dropped from 35.5 to 3.8 per 10,000 ectopic

pregnancies. [5 ]If the overall incidence of ectopic pregnancy remained stable in the 1990s, then

the mortality rate dropped to 3.19 per 10,000 ectopic pregnancies by 1999.[11 ]The mortality rate

reported in African hospital-based studies varies from 50-860 per 10,000 ectopic pregnancies;

these are almost certainly underestimates due to underreporting of maternal deaths and

misclassification of ectopic pregnancies as induced abortions.[9 ]

Surveillance data for pregnancy-related deaths in the United States from 1991-1999 showed

that ectopic pregnancy was the cause of 5.6% of 4,200 maternal deaths. Of these deaths, 93%

occurred via hemorrhage.[12 ]Using data from 1997-2002, the World Health Organization (WHO)

estimated that ectopic pregnancy was the cause of 4.9% of pregnancy-related deaths in the

developed world.[13 ]Ectopic pregnancy caused 26% of maternal deaths in early pregnancy in the

United Kingdom from 2003-2005, second only to venous thromboembolism, despite a relatively

low mortality rate of 0.035 per 10,000 estimated ectopic pregnancies.[10 ]

Race

In the United States from 1991-1999, ectopic pregnancy was the cause of 8% of all pregnancy-

related deaths of African American women compared with 4% for white women. [12 ]

Sex

Any woman with functioning ovaries can potentially have an ectopic pregnancy.

Age

Any woman from the age of menarche until menopause can potentially have an ectopic

pregnancy. Women older than 40 years were found to have an adjusted odds ratio of 2.9 (95%

confidence interval [CI], 1.4-6.1) for ectopic pregnancy.[14 ]


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Clinical

History

The classic triad of symptoms in ectopic pregnancy is abdominal pain, amenorrhea, and vaginal

bleeding, but fewer than half of patients present with all 3 symptoms. In one case series of

ectopic pregnancies, abdominal pain presented in 98.6%, amenorrhea in 74.1%, and irregularvaginal bleeding in 56.4%.[15 ]These symptoms overlap with those of spontaneous abortion; a

prospective consecutive case series found no statistically significant differences in the

presenting symptoms of patients with unruptured ectopic pregnancies versus those with

intrauterine pregnancies.[16 ]

In first-trimester symptomatic patients, pain as the presenting symptom is associated with an

odds ratio of 1.42 (95% CI, 1.06-1.92), and moderate-to-severe vaginal bleeding at presentation

is associated with an odds ratio of 1.42 (95% CI, 1.04-1.93) for ectopic pregnancy. [17 ]In one

study, 9% of patients with ectopic pregnancy presented with painless vaginal bleeding. [18 ]

Other presenting complaints may be nonspecific such as painful fetal movements (in the case ofadvanced abdominal pregnancy), dizziness or weakness, fever, flu-like symptoms, vomiting,

syncope, or cardiac arrest. Shoulder pain may be reflective of peritoneal irritation.

In a review of deaths from ectopic pregnancy in Michigan, 44% were either found dead at home

or were dead on arrival at the emergency department.[19 ]

Physical

The physical examination of patients with ectopic pregnancy is highly variable and often

unhelpful. Patients frequently present with benign examination findings, and adnexal masses

are rarely found. Patients in hemorrhagic shock from ruptured ectopic may not be tachycardic.[20

]

Some physical findings that have been found to be predictive (although not diagnostic) for

ectopic pregnancy were the presence of peritoneal signs, cervical motion tenderness, and

unilateral or bilateral abdominal or pelvic tenderness. However, midline abdominal tenderness

or a uterine size of greater than 8 weeks on pelvic examination decreases the risk of ectopic

pregnancy. [21 ]

The presence of uterine contents in the vagina, which can be caused by shedding of

endometrial lining stimulated by an ectopic pregnancy, may lead to a misdiagnosis of an

incomplete or complete abortion and therefore a delayed or missed diagnosis of ectopic

pregnancy.

Causes

An ectopic pregnancy requires the occurrence of 2 events: fertilization of the ovum and

abnormal implantation. Many risk factors affect both events; for example, history of major tubal

infection decreases fertility and increases abnormal implantation. Major risk factors include

previous ectopic pregnancy, previous tubal surgery, documented tubal pathology, and maternal

in utero DES exposure.


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Previous treatment of pelvic infections (whether documented or not), 2 or more years of

infertility (whether treated or not), and multiple sexual partners were associated with mildly

elevated risk.[22 ]A large case-control study in France found that about one third of cases could

be attributed to smoking (presumably by impairing tubal motility), one-third to infectious history

and prior tubal surgery (considered together), 18% to a history of infertility, and 14% to maternal

age (although this is not an independent risk factor); 24% had no attributable risk factors. [14

]Women using assisted reproduction seem to have a doubled risk of ectopic pregnancy (to 4%),

although this is mostly due to the underlying infertility.[23 ]

All contraceptive methods lead to an overall lower risk of pregnancy, and therefore also an

overall lower risk of ectopic pregnancy. However, among cases of contraceptive failure, women

at increased risk of ectopic pregnancy compared with pregnant controls include those using

progestin-only oral contraceptives, progestin-only implants, or intrauterine devices (IUDs), and

those with a history of tubal ligation.[24 ]In one study, 33% of pregnancies occurring after tubal

ligation were ectopic; those who underwent electrocautery and women younger than 35 years

were at higher risk.[25 ]Emergency contraception (levonorgestrel, or Plan B) does not appear to

lead to a higher-than-expected rate of ectopic pregnancy.[26 ]A recent literature review found 56

reported cases of ectopic pregnancy (by definition) after hysterectomy, dating back to 1937.[27 ]

Other causes of ectopic pregnancy include anatomic abnormalities of the uterus such as a

bicornuate uterus, fibroids or other uterine tumors, or endometriosis; or abnormalities of the

tubes such as salpingitis isthmica nodosa or tubal ligation reversal. Appendicitis has also been

found to be a risk factor for ectopic pregnancy.[14 ]

Differential Diagnoses

Abortion, Complications Pediatrics, Appendicitis

Appendicitis, Acute Placenta Previa

Dysmenorrhea Shock, HemorrhagicEarly Pregnancy Loss Shock, Hypovolemic

Other Problems to Be Considered

Abortion, postabortion bleeding

Abortion, retained products

Ruptured corpus luteum cyst

Cornual myoma or abscess

Ovarian tumor

Endometrioma

Cervical cancer

Cervical phase of uterine abortion

Workup

Laboratory Studies

Diagnosis of ectopic pregnancy has been greatly improved by the advent of rapid serum beta-

human chorionic gonadotropin (beta-HCG) tests in the early 1980s and then the widespread

adoption of transvaginal pelvic ultrasonography (TVUS) in the late 1980s.[28 ]Starting in the mid-


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1990s, the rise of bedside ultrasonography performed by emergency physicians has brought

further improvements in time to diagnosis and treatment. Currently, the approach focuses on

diagnosing ruptured or suspected ectopic pregnancy versus normal (or failing) intrauterine

pregnancy using early TVUS in the emergency department, then obtaining a serum beta-HCG

level on patients with indeterminate sonogram results (also known as pregnancies of unknown

location, or PUL),[29 ]with the aim of close outpatient follow-up of serial beta-HCG levels and

sonograms.

The first laboratory test to obtain is a qualitative urine beta-human chorionic gonadotropin (uCG)

test, which can be performed rapidly at bedside. The uCG can be unreliable at low quantitative

serum beta-HCG levels (ie,


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y Complete blood count, if significant hemorrhage is suspected

y Metabolic panel to rule out electrolyte imbalances and also to rule out hepatic or renal

abnormalities in case methotrexate therapy is being considered

y Serum lactate level in cases of suspected shock

y Urinalysis to eliminate urinary tract infection as a cause of pelvic pain

y Blood type and Rh factor, if transfusion is required and also to provide RhoGAM for Rh-

negative patients with vaginal bleeding

Imaging Studies

Ultrasonography

Bedside pelvic sonography is the imaging test of choice to investigate early pregnancy

complaints in the emergency department. It is noninvasive, portable, repeatable, does not

involve contrast or ionizing radiation, and can be performed concurrently with resuscitation of an

unstable patient. The goals of bedside pelvic ultrasonography are to find a definitive intrauterine

pregnancy (IUP), a definitive or suspected ectopic pregnancy, and findings indicative of failed

IUP. Because sonogram findings of early normal IUP development (


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y An extrauterine sac containing a yolk sac or a fetal pole, with or without heart motion:

Although definitive for ectopic pregnancy, only 16-32% of ectopics have this finding on

transvaginal sonogram.[43 ]

y

An endovaginal sonogram reveals a complex mass outside of the uterus with a small

yolk sac present within. The mass is more echogenic than the uterus above it and

represents an ectopic pregnancy.

y Tubal ring: This is a thick-walled cystic structure in the adnexa, independent of the ovary

and uterus, and is highly predictive of ectopic pregnancy.[44 ]It can sometimes be

confused with a corpus luteum cyst when the ovary is not well visualized. The corpus

luteum cyst wall tends to be thinner and less echogenic than the endometrium, and the

cyst tends to contain clear fluid.[45 ]When surrounded by free fluid, it can sometimes be

confused with a hemorrhagic ovarian cyst.[46 ]y A complex adnexal mass: This is the sign most frequently found in ectopic

pregnancies. [47 ]It can be somewhat cystic-appearing or entirely solid in nature,

surrounded by free fluid, and ill-defined. If it cannot be moved independently of the

ovary, it is unlikely to be an ectopic pregnancy.[48 ]

y A moderate amount of free fluid (or any echogenic fluid): The cul-de-sac or pouch of

Douglas must be assessed when a definitive IUP is absent. A small amount of free fluid

can be seen physiologically. A moderate amount of anechoic free fluid (tracking more

than one third of the way up the posterior wall of the uterus), or any echogenic free fluid,

has a higher chance of being ultimately diagnosed as an ectopic pregnancy. [49 ]

y Double decidual sac sign, or gestational sac


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A pseudogestational sac of an ectopic pregnancy can be confused with embryonic

demise. A pseudogestational sac is produced when an ectopic pregnancy stimulates

the endometrium, with degeneration of the central decidual reaction.

y Empty uterus without any of the above adnexal findings: This may be indicative of an

early IUP, completed abortion, or an ectopic pregnancy. In this case, a beta-HCG above

the discriminatory zone essentially rules out an early IUP, although it does not help rulein or out ectopic pregnancy. A thin endometrial stripe (


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Dilation and curettage (D&C) can be used to rule out ectopic pregnancy by determining the

presence of chorionic villi. The obvious drawback to its frequent use is that a certain number of

normal IUPs will be aborted. It may be an option in the further workup of PUL when the

pregnancy is undesired.

Treatment

Prehospital Care

Patients in shock require prehospital care to treat hypotension.

Emergency Department Care

The most critical step in beginning the workup is to have a high clinical suspicion for ectopic

pregnancy (eg, in any woman of childbearing age). After a positive urine pregnancy test, any

necessary initial resuscitation, and physical examination (including pelvic examination to rule

out an open cervical os or completed abortion), a transabdominal pelvic ultrasonography,

followed by a transvaginal ultrasonography if needed, should be performed to identify a

definitive intrauterine pregnancy (yolk sac or fetal pole) or definitive ectopic pregnancy(extrauterine yolk sac or fetal pole).

This initial sonogram should be obtained at bedside by an emergency physician, where feasible.

A protocol using bedside emergency physician-performed transvaginal ultrasonography showed

a large reduction in the incidence of discharged patients who later had ruptured ectopic

pregnancies. [55 ]Emergency physician-performed ultrasonography has been shown to speed time

to diagnosis compared to ultrasonography performed by an OB/GYN consult [56 ]or by the

radiology department[57 ]. Experienced emergency physicians are sometimes able to correctly

diagnose ectopic pregnancies initially missed by OB/GYN consults. [58 ]The only lawsuit found in

a search of the WESTLAW nationwide litigation database concerning emergency physicians

and ultrasonography was filed for failure to perform ED ultrasonography in an ectopic pregnancy

that ruptured several days later.[59 ]

Hemodynamically unstable patients should first be scanned in the right upper quadrant of the

abdomen, as the finding of free fluid in Morison's pouch in the right clinical setting by the

emergency physician has been shown to decrease time to the operating room. [60 ]Attention

should be paid to the adnexa, even when an intrauterine pregnancy (IUP) is visualized, to rule

out the rare heterotopic pregnancy, especially in patients with a history of assisted reproduction.

Ultrasonographic findings suggestive of ectopic pregnancy (empty uterus with a tubal ring,

complex adnexal mass, or a moderate-to-large amount of free fluid), or a definite extrauterine

pregnancy, warrant an immediate GYN consult for medical or surgical treatment. Patients with

evidence of a failed IUP should be followed up in consultation with GYN for either repeatultrasonography and serial beta-HCG, D&C, or expectant management.

Patients with indeterminate sonogram findings (empty uterus, gestational sac


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surgical treatment.[61 ]Patients with a live IUP on sonogram are essentially ruled out for ectopic

pregnancy, have a low risk of eventually aborting (about 9% in one study, higher if associated

with vaginal bleeding[62 ]), and can be discharged from the ED after routine further care.

Consultations

OB/GYN should be consulted as needed for ectopic pregnancies, and follow-up care of patientswith failing/failed IUPs or pregnancies of unknown location. Any patient who is clinically unstable

should have the consultation in the emergency department.

OB/GYN or radiology should also be consulted for transvaginal sonography as needed,

according to institutional policy.

Medication

The current standard medical treatment of unruptured ectopic pregnancy is methotrexate (MTX)

therapy.[63 ]This decision should be made in conjunction with, if not by, the consulting OB/GYN.

The ideal candidate for medical treatment should have (1) hemodynamic stability, (2) no severe

or persisting abdominal pain, (3) ability to follow-up multiple times, and (4) normal baseline liver

and renal function tests. Absolute contraindications include existence of intrauterine pregnancy

(IUP), immunodeficiency, moderate-to-severe anemia, leucopenia, or thrombocytopenia,

sensitivity to MTX, active pulmonary or peptic ulcer disease, clinically important hepatic or renal

dysfunction, or breastfeeding.

Sonogram findings of an ectopic gestational sac greater than 4 cm in size, (or 3.5 cm if the

ectopic pregnancy has fetal heart motion), an initial beta-HCG concentration of greater than

5000 mIU/mL, or significant free fluid are indicators of likely failure of MTX therapy and therefore

relative contraindications.

The multiple-dose regimen of methotrexate consists of daily doses of 1 mg/kg IM, given onalternating days with leucovorin (folinic acid, which reduces side effects), until there is a 15%

decline in beta-HCG over 2 days. The single-dose regimen consists of one dose of

methotrexate 50 mg/m2, followed by a repeat beta-HCG at day 4, and another dose of MTX 50

mg/m2 if the beta-HCG has declined less than 15% between days 4 and 7. Both treatment

regimens show an efficacy similar to surgical management for unruptured ectopic pregnancies

in the ideal patient population. Common side effects include increase in abdominal girth, vaginal

bleeding or spotting, abdominal pain, GI symptoms, stomatitis, dizziness. Rare side effects

include severe neutropenia, reversible alopecia, or pneumonitis. [63 ]

Anti-Metabolite

These agents are used to terminate pregnancy.

Methotrexate (Folex, PFS)

Used for treatment of unruptured tubal pregnancy and for persistent disease after

salpingostomy.


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Dosing

Adult

1 mg/kg IM qod with leucovorin 0.1 mg/kg IM between doses; not to exceed 4 doses

Pediatric

12 years: Administer as in adults

Interactions

Oral aminoglycosides may decrease absorption and blood levels of concurrent oral

methotrexate (MTX); charcoal lowers levels; coadministration with etretinate may increase

hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease

response; coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can

increase MTX plasma levels; may decrease phenytoin serum levels; probenecid, salicylates,

procarbazine, and sulfonamides (including TMP-SMZ) may increase effects and toxicity of MTX;

may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency

syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia,

thrombocytopenia, significant anemia)

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

PrecautionsToxic hematologic, renal, GI, pulmonary, and neurologic effects

Follow-up

Further Inpatient Care

Patients with ectopic pregnancy who require admission or surgery should be admitted to an

OB/GYN service.

Further Outpatient Care

Patients with pregnancy of unknown location should follow up with OB/GYN in 2 days for repeat

beta-HCG and ultrasonography.

Patients with failing or failed IUPs should arrange for follow-up with OB/GYN for D&C or

expectant management.

Patients receiving methotrexate in the emergency department should follow up with OB/GYN as

per protocol.


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Transfer

Patients who have sonogram findings suggestive of ectopic pregnancy or those who are

clinically unstable at a location where pelvic sonography is unavailable should be transferred to

a facility that provides a higher level of care.

Deterrence/Prevention

Contraception reduces the rate of ectopic pregnancies.

Public health efforts to reduce the community prevalence of STDs may also reduce the rate of

tubal scarring and therefore ectopic pregnancies.

Complications

Complications of ectopic pregnancy may include the following:

y Hemorrhage

y Hypovolemic shock

y Infectiony Infertility (secondary to loss of reproductive organs after surgery)

y Other complications associated with surgery

Prognosis

Patients who are diagnosed with ectopic pregnancy before rupture have a low mortality rate and

also a chance at preserved fertility.

Patient Education

Patients with risk factors for ectopic pregnancy should be educated regarding their risk of future

ectopic pregnancies.

Patients undergoing assisted reproduction should be educated regarding their risk of

heterotopic pregnancy.

Patients who are being discharged with a pregnancy of unknown location should be educated

regarding the possibility of ectopic pregnancy and their need for urgent follow-up.

Patients being medically treated for ectopic pregnancy should be counseled about the likelihood

of side effects and the need to return to the emergency department for concerning symptoms.

Miscellaneous

Medicolegal Pitfalls

Failure to consider ectopic pregnancy as a diagnosis

Failure to get a serum beta-HCG level in cases where the uCG is negative but the clinical

suspicion is high


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Failure to correctly perform or interpret a bedside ultrasonography results (ie, mistaking a

pseudogestational sac for an IUP, mistaking an interstitial pregnancy for an IUP)

Failure to consider a heterotopic pregnancy in a patient undergoing assisted reproduction

Failure to consult GYN in cases when the patient is unstable or when the sonogram findings are

uncertain or suggestive of ectopic pregnancy

Failure to check Rh status and give RhoGAM to patients with vaginal bleeding, even those with

ectopic pregnancies

Failure to arrange prompt follow-up for patients with pregnancy of unknown location

Multimedia

Media file 1: Pregnancy, ectopic. An endovaginal sonogram reveals an intrauterine

pregnancy at approximately 6 weeks. A yolk sac (ys), gestational sac (gs), and fetal pole

(fp) are depicted.


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Media file 2: An endovaginal sonogram demonstrates an early ectopic pregnancy. An

echogenic ring (tubal ring) found outside of the uterus can be seen in this view.

Media file 3: An endovaginal sonogram reveals a complex mass outside of the uterus with a

small yolk sac present within. The mass is more echogenic than the uterus above it and

represents an ectopic pregnancy.

Media file 4: A pseudogestational sac of an ectopic pregnancy can be confused with

embryonic demise. A pseudogestational sac is produced when an ectopic pregnancy

stimulates the endometrium, with degeneration of the central decidual reaction.

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