Ectopic pregnancy can cause life-threatening hemorrhage, and if it is suspected, the patient should be evaluated and treated as soon as possible. Incidence of ectopic pregnancy is approximately 2/100 diagnosed pregnancies (1). Patients with possible ectopic pregnancy or other cause of early pregnancy failure often present with symptoms early in pregnancy, when ultrasonography is not able to confirm the anatomic location or viability of the pregnancy. Therefore, these pregnancies are referred to as pregnancy of unknown location.
General reference
1. Van Den Eeden SK, Shan J, Bruce C, Glasser M: Ectopic pregnancy rate and treatment utilization in a large managed care organization. Obstet Gynecol 105 (5 Pt 1):1052–1057, 2015. doi: 10.1097/01.AOG.0000158860.26939.2d
Etiology of Ectopic Pregnancy
Most ectopic pregnancies are located in the fallopian tube, and any history of infection or surgery that increases the risk of tubal adhesions or other abnormalities increases risk of ectopic pregnancy.
Factors that particularly increase risk of ectopic pregnancy include
Prior ectopic pregnancy
Prior pelvic surgery, particularly tubal surgery, including tubal sterilization
Tubal abnormalities or damage (eg, due to ascending infection or surgery)
Assisted reproductive technologies used in current pregnancy, particularly with history of tubal infertility or multiple embryo transfer
Other risk factors for ectopic pregnancy include
History of pelvic inflammatory disease or sexually transmitted infections (particularly due to Chlamydia trachomatis)
Cigarette smoking
Overall, becoming pregnant is much less likely in patients who have had tubal sterilization or have an intrauterine device (IUD) in place; however, when pregnancy does occur in these patients, risk of ectopic pregnancy is increased (eg, approximately 53% in pregnancies in current IUD users) (1).
Etiology reference
1. Backman T, Rauramo I, Huhtala S, Koskenvuo MAm J Obstet Gynecol 190(1):50-54, 2004. doi:10.1016/j.ajog.2003.07.021
Pathophysiology of Ectopic Pregnancy
The most common site of ectopic implantation is a fallopian tube, followed by the uterine cornua (referred to as a cornual or an interstitial pregnancy). Pregnancies implanted in the cervix, a cesarean scar, an ovary, or the abdomen are rare.
Heterotopic pregnancy (simultaneous ectopic and intrauterine pregnancies) occurs in only 1/10,000 to 30,000 pregnancies but may be more common among women who have had ovulation induction or used assisted reproductive technologies such as in vitro fertilization and gamete intrafallopian tube transfer (GIFT); in these women, the overall reported ectopic pregnancy rate is 1 to 2% (1).
The anatomic structure containing the fetus usually ruptures after about 6 to 16 weeks. Rupture results in bleeding that can be gradual or rapid enough to cause hemorrhagic shock. The later in the pregnancy the rupture occurs, the more rapidly blood is lost and the higher the risk of death.
Pathophysiology reference
1. Perkins KM, Boulet SL, Kissin DM, et al: Risk of ectopic pregnancy associated with assisted reproductive technology in the United States, 2001-2011. Obstet Gynecol 125 (1):70–78, 2015. doi: 10.1097/AOG.0000000000000584
Symptoms and Signs of Ectopic Pregnancy
Symptoms of ectopic pregnancy vary and may be absent until rupture occurs.
Most patients have pelvic pain (which can be dull, sharp, or crampy), vaginal bleeding, or both. Patients who have irregular menses may not be aware that they are pregnant.
Rupture may be heralded by sudden, severe pain, followed by syncope or by symptoms and signs of hemorrhagic shock or peritonitis. Rapid hemorrhage is more likely in ruptured cornual pregnancies.
Cervical motion tenderness, unilateral or bilateral adnexal tenderness, or an adnexal mass may be present. Pelvic examination should be done carefully because excessive pressure may rupture the pregnancy. The uterus may be slightly enlarged (but often less than anticipated based on date of the last menstrual period).
Diagnosis of Ectopic Pregnancy
Pelvic ultrasonography
Sometimes laparoscopy
Ectopic pregnancy is suspected in any female patient of reproductive age with pelvic pain, vaginal bleeding, or unexplained syncope or hemorrhagic shock, regardless of menstrual, contraceptive, and sexual history. Findings of physical (including pelvic) examination are neither sensitive nor specific.
A ruptured ectopic pregnancy is a surgical emergency because it causes maternal hemorrhage and risk of death; prompt diagnosis is essential.
Pearls & Pitfalls
|
The first step in diagnosis is a urine pregnancy test, which is approximately 99% sensitive for pregnancy (ectopic and otherwise). If urine beta-hCG is negative and if clinical findings do not strongly suggest ectopic pregnancy, further evaluation is unnecessary unless symptoms recur or worsen. If urine beta-hCG is positive or if clinical findings strongly suggest ectopic pregnancy and pregnancy may be too early to detect based on urine beta-hCG, quantitative serum beta-hCG and pelvic ultrasonography should be done.
If ultrasonography detects an intrauterine pregnancy, a concurrent ectopic pregnancy (heterotopic pregnancy) is extremely unlikely except in women who have used assisted reproductive technologies (which increase risk of heterotopic pregnancy, although it is still rare in these patients). However, cornual and interstitial pregnancies may appear to be intrauterine pregnancies on ultrasound.
Ultrasonographic findings diagnostic of an intrauterine pregnancy are a gestational sac with a yolk sac or an embryo (with or without a heartbeat) within the uterine cavity. In addition to absence of an intrauterine pregnancy, ultrasonographic findings suggesting ectopic pregnancy include a complex (mixed solid and cystic) pelvic mass, particularly in the adnexa, and echogenic free fluid in the cul-de-sac.
If serum beta-hCG is above a certain level (called the discriminatory zone), ultrasonography should be able to detect a gestational sac with a yolk sac; the presence of a yolk sac confirms an intrauterine pregnancy. The appropriate hCG threshold for the discriminatory zone for women with suspected ectopic pregnancy has been reevaluated. To minimize overdiagnosis of ectopic pregnancy and preserve desired intrauterine pregnancies, the recommended threshold has been increased to 3500 mIU/mL) (1).
If the beta-hCG level is below the discriminatory zone and ultrasonography is unremarkable, patients may have an early intrauterine pregnancy or an ectopic pregnancy. If clinical evaluation suggests ectopic pregnancy with active bleeding or rupture (eg, signs of significant hemorrhage or peritoneal irritation), diagnostic laparoscopy may be necessary for diagnosis and treatment.
If ectopic pregnancy has not been confirmed and the patient is stable, serum levels of beta-hCG are measured serially on an outpatient basis (typically every 2 days). Normally, the level doubles every 1.4 to 2.1 days up to 41 days; in ectopic pregnancy (and in potential spontaneous abortions), levels may be lower than expected by dates and usually do not double as rapidly. If beta-hCG levels do not increase as expected or if they decrease, diagnosis of spontaneous abortion or ectopic pregnancy is likely.
Differential diagnosis
Bleeding is common in early pregnancy (see table Some Causes of Vaginal Bleeding During Early Pregnancy for differential diagnosis).
Some Causes of Vaginal Bleeding During Early Pregnancy
Cause | Suggestive Findings | Diagnostic Approach* |
|---|---|---|
Obstetric disorders | ||
Vaginal bleeding with or without abdominal or pelvic pain (often sudden, localized, and constant, not crampy) Closed cervical os No fetal heart sounds Possible hemodynamic instability if ectopic pregnancy is ruptured Sometimes, a palpable adnexal mass | Quantitative beta-hCG measurement, repeated every 2 days if diagnosis is uncertain Complete blood count Pelvic ultrasonography Sometimes, endometrial sampling Laparoscopy or, if the patient is hemodynamically unstable, laparotomy | |
Threatened abortion | Vaginal bleeding with or without crampy abdominal pain Closed cervical os | Fetal heart rate auscultation Quantitative beta-hCG measurement Complete blood count Pelvic ultrasonography |
Inevitable abortion | Vaginal bleeding with crampy abdominal pain Open cervical os (dilated cervix) | Evaluation as for threatened abortion |
Incomplete abortion | Vaginal bleeding with crampy abdominal pain Open or closed cervical os Products of conception often seen or felt through os | Evaluation as for threatened abortion |
Complete abortion | Mild vaginal bleeding at presentation but usually a history of significant vaginal bleeding immediately preceding visit; sometimes, with mild, crampy abdominal pain Closed cervical os; uterus is nonpregnant size | Evaluation as for threatened abortion |
Usually, history of recent induced or spontaneous abortion (risk is higher if induced abortion is performed without appropriately trained clinicians and equipment or if self-induced) Fever, chills, constant abdominal or pelvic pain Vaginal bleeding and/or purulent vaginal discharge Uterine tenderness Open cervical os | Evaluation as for threatened abortion plus evaluation for STIs and vaginitis | |
Gestational trophoblastic disease (hydatidiform mole) | Vaginal bleeding, with or without crampy abdominal pain Larger-than-expected uterine size, often elevated blood pressure, severe vomiting If more advanced, sometimes passage of grapelike tissue from the vagina | Evaluation as for threatened abortion plus thyroid tests, creatinine, liver tests, chest x-ray |
Ruptured corpus luteum cyst | Localized abdominal pain, vaginal bleeding, sometimes nausea and vomiting Sudden onset of symptoms | Evaluation as for ectopic pregnancy |
Gynecologic or other disorders | ||
Trauma | History or suspicion of physical trauma (eg, motor vehicle accident, laceration of the cervix or vagina due to instrumentation or sexual assault, sometimes a complication of chorionic villus sampling or amniocentesis) | Complete blood count Pelvic ultrasonography (to evaluate fetus) Other imaging studies (to evaluate for injury or internal bleeding) Questions about possible intimate partner violence or sexual assault, if suspected |
Spotting or scant bleeding with vaginal discharge Sometimes, dyspareunia | Evaluation for vaginitis and STIs | |
Mucopurulent cervical discharge Sometimes, scant vaginal bleeding Sometimes, cervical motion tenderness, abdominal pain, or both | Evaluation for STIs and vaginitis | |
Scant vaginal bleeding, no pain Polypoid mass protruding from cervix | Pelvic examination Histology of specimen after biopsy or removal | |
Beta-hCG = | ||
* Evaluation of concerning symptoms in all pregnant patients should include assessment of maternal vital signs, physical examination, and evaluation of fetal status with fetal heart rate monitoring or ultrasonography. | ||
Pelvic pain or pressure is also a common pregnancy symptom (see table Some Causes of Pelvic Pain During Early Pregnancy for differential diagnosis).
Some Causes of Pelvic Pain During Early Pregnancy
Cause | Suggestive Findings | Diagnostic Approach* |
|---|---|---|
Obstetric disorders | ||
Normal changes of pregnancy, including those due to stretching and growth of the uterus and surrounding connective tissues | Crampy sensation or pressure in the lower abdomen, pelvis, lower back, or a combination Sometimes, with movement, sudden sharp pain (round ligament pain) | Routine prenatal evaluation with maternal vital signs, abdominal examination, sometimes pelvic examination, and fetal heart rate auscultation (depending on gestational age) Sometimes, pelvic ultrasonography Evaluation for ectopic pregnancy or other conditions, if suspected |
Abdominal or pelvic pain, which is often sudden, localized, and constant (not crampy), usually with vaginal bleeding Closed cervical os No fetal heart sounds Possibly hemodynamic instability if ectopic pregnancy has ruptured Sometimes, a palpable adnexal mass | Quantitative beta-hCG measurement, repeated every 2 days if diagnosis is uncertain Complete blood count Pelvic ultrasonography Sometimes, endometrial sampling Laparoscopy or, if the patient is hemodynamically unstable, laparotomy | |
Spontaneous abortion (threatened, inevitable, incomplete, complete, missed) | Crampy, diffuse, lower abdominal pain, often with vaginal bleeding Open or closed cervical os depending on the type of abortion (see table Some Causes of Vaginal Bleeding) | Fetal heart rate auscultation Quantitative beta-hCG measurement, repeated every 2 days if diagnosis is uncertain Complete blood count Pelvic ultrasonography |
Usually, history of recent induced or spontaneous abortion (risk is higher if induced abortion is performed without appropriately trained clinicians and equipment or if self-induced) Fever, chills, constant abdominal or pelvic pain Vaginal bleeding and/or purulent vaginal discharge Uterine tenderness Open cervical os | Evaluation as for spontaneous abortion plus evaluation for STIs and vaginitis | |
Gynecologic disorders | ||
Uterine fibroid degeneration | Sudden onset of pelvic pain, dull or sharp, usually severe, often with nausea, vomiting, and fever Sometimes, vaginal bleeding Uterine tenderness | Ultrasonography MRI (used only if diagnosis is uncertain) |
Sudden onset of localized pelvic pain, which may be severe and intermittent (if torsion spontaneously resolves) Often, nausea, vomiting | Doppler ultrasonography | |
Ruptured corpus luteum cyst | Localized abdominal or pelvic pain Sometimes, vaginal bleeding Usually, sudden onset | Ultrasonography Complete blood count |
Pelvic inflammatory disease (uncommon during pregnancy) | Purulent cervicovaginal discharge Significant cervical motion, uterine, and/or adnexal tenderness Often, fever and/or abnormal vaginal bleeding | Evaluation for STIs and vaginitis White blood cell count |
Benign or malignant ovarian tumor | Dull abdominal pain or pressure Sometimes, weight loss Sometimes, abdominal distension and ascites Sometimes, ovarian cancer risk factors | Ultrasonography Tumor markers Sometimes, diagnostic laparoscopy |
Ovarian hyperstimulation syndrome | Use of fertility medications for current pregnancy Dull abdominal pain or pressure If moderate or severe, weight gain, abdominal distension and ascites, acute kidney disease, pleural effusion, or disseminated intravascular coagulation | Ultrasonography Complete blood count Comprehensive metabolic panel |
Nongynecologic disorders | ||
Usually, continuous diffuse or localized abdominal pain, tenderness Possibly atypical location (eg, right upper quadrant) or qualities (milder, crampy, no peritoneal signs) compared with pain in nonpregnant patients; appendix may be in a different position due to enlarged uterus Sometimes, peritoneal signs Sometimes, nausea, vomiting, or loss of appetite | Pelvic/abdominal ultrasonography, followed by MRI if ultrasonography is inconclusive; consideration of CT if MRI is not readily available White blood cell count or C-reactive protein | |
Suprapubic discomfort, often with bladder symptoms (eg, burning, frequency, urgency) Sometimes, fever, chills, and/or flank pain (risk of pyelonephritis is increased in pregnancy) | Urinalysis and culture | |
Variable pains (crampy or constant) in no consistent location, often with diarrhea and sometimes with mucus or blood Sometimes, fever Usually, a known history of IBD | Sometimes, fecal calprotectin Sometimes, endoscopy | |
Acute nausea and vomiting, usually in patients who have had abdominal surgery, have an intraabdominal malignancy, or sometimes an incarcerated hernia detected during examination Colicky pain, vomiting, no bowel movements or flatus Distended, tympanitic abdomen Usually, history of abdominal surgery (causing adhesions), have an intraadominal malignancy, or sometimes an incarcerated hernia detected during examination May be caused by or occur in patients with appendicitis | Evaluation as for ectopic pregnancy Abdominal imaging with flat and upright x-rays, ultrasonography, and possibly CT (if x-ray and ultrasonography results are equivocal) | |
Usually, vomiting, diarrhea No peritoneal signs | Sometimes, stool tests (if bacterial or parasitic infection is suspected) | |
Beta-hCG = beta subunit of human chorionic gonadotropin; STIs = sexually transmitted infections. | ||
* Evaluation of concerning symptoms in all pregnant patients should include assessment of maternal vital signs, physical examination, and evaluation of fetal status with fetal heart rate monitoring or ultrasonography. | ||
Diagnosis reference
1. Doubilet PM, Benson CB, Bourne T, et al: Diagnostic criteria for nonviable pregnancy early in the first trimester. N Engl J Med 369(15):1443-1451, 2013. doi:10.1056/NEJMra1302417
Treatment of Ectopic Pregnancy
Rho(D) immune globulin if the woman is Rh-negative
Methotrexate
The American College of Obstetricians and Gynecologistsabsolute contraindications is present:
Intrauterine pregnancy
Ruptured ectopic pregnancy
Hemodynamically unstable
Evidence of immunodeficiency
Moderate to severe anemia, leukopenia, or thrombocytopenia
Active pulmonary disease or peptic ulcer disease
Clinically important hepatic or renal dysfunction
Breastfeeding
Unable to participate in follow-up surveillance
Additionally, the following relative contraindications should be considered:
Embryonic cardiac activity detected by transvaginal ultrasonography
High initial hCG concentration
Ectopic pregnancy > 4 cm in size (as imaged on transvaginal ultrasonography)
Refusal to accept blood donation
methotrexate or surgery is needed. Alternatively, other protocols can be used.
The beta-hCG level is then measured weekly until it is undetectable. Success rates with methotrexate are approximately 90%; 9% of women have complications that require hospitalization (1).
Usually, methotrexate can be used, but surgery is indicated when rupture is suspected, the patient is not able to comply with follow-up surveillance after methotrexate therapy, or methotrexate is ineffective.
Surgical resection
Hemodynamically unstable patients require immediate laparotomy and treatment of hemorrhagic shock.
For stable patients, surgical treatment is usually laparoscopic surgery; sometimes laparotomy is required. If possible, salpingotomy is done to conserve the tube, and the ectopic pregnancy is removed.
Salpingectomy is indicated in any of the following cases:
The ectopic pregnancy has ruptured.
Hemorrhage continues after salpingotomy.
The tube has been reconstructed.
The ectopic pregnancy represents a failure of a previous sterilization procedure, particularly if the pregnancy is in the blind-ending distal segment in women who have had a previous partial salpingectomy.
Only the irreversibly damaged portion of the tube is removed, maximizing the chance that tubal repair can restore fertility. The tube may or may not be repaired. After a cornual pregnancy, the tube and ovary involved can usually be salvaged, but occasionally repair is impossible, making hysterectomy necessary.
All patients who are Rh-negative, whether managed with methotrexate or surgery, are given Rho(D) immune globulin.
Treatment reference
1. Barnhart KT, Gosman G, Ashby R, Sammel M: The medical management of ectopic pregnancy: a meta-analysis comparing "single dose" and "multidose" regimens. Obstet Gynecol 101(4):778-784, 2003. doi:10.1016/s0029-7844(02)03158-7
Prognosis for Ectopic Pregnancy
Ectopic pregnancy is fatal to the fetus, but if treatment occurs before rupture, maternal death is rare. In the United States in 2018, the mortality rate due to ectopic pregnancies was 0.8 deaths per 100,0000 live births (1).
Prognosis reference
1. Hoyert DL, Miniño AM: Maternal mortality in the United States. Changes in coding, publication, and data release, 2018. National Vital Statistics Reports; vol 69 no 2. Hyattsville, MD: National Center for Health Statistics. 2020.
Key Points
Ectopic pregnancy is the implantation of a pregnancy in a site other than the endometrial lining of the uterine cavity; the most common site for ectopic pregnancies is a fallopian tube.
Symptoms can include pelvic pain and vaginal bleeding in a pregnant woman, but the woman may not be aware she is pregnant and symptoms may be absent until rupture occurs, sometimes with catastrophic results.
Suspect ectopic pregnancy in any female of reproductive age with pelvic pain, vaginal bleeding, or unexplained syncope or hemorrhagic shock.
If a urine pregnancy test is positive or clinical findings suggest ectopic pregnancy, determine quantitative serum beta-hCG and do pelvic ultrasonography.
