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 General reference Ectopic pregnancy is the implantation of a pregnancy in a site other than the endometrial lining of the uterine cavity—ie, in the fallopian tube, uterine cornua, cervix, ovary, or abdominal... read more ). 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.
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 Sterilization In the United States, one third of couples attempting to prevent pregnancy, particularly if the woman is > 30 years old, choose permanent contraception with vasectomy or tubal sterilization... read more
Tubal abnormalities or damage (eg, due to ascending infection or surgery)
Assisted reproductive technologies Assisted Reproductive Technologies Assisted reproductive technologies (ARTs) involve manipulation of sperm and ova or embryos in vitro with the goal of producing a pregnancy. For assisted reproductive technologies, oocytes and... read more 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 Pelvic Inflammatory Disease (PID) Pelvic inflammatory disease (PID) is a polymicrobial infection of the upper female genital tract: the cervix, uterus, fallopian tubes, and ovaries; abscess may occur. PID may be caused by sexually... read more or sexually transmitted infections Overview of Sexually Transmitted Infections Sexually transmitted infection (STI) refers to infection with a pathogen that is transmitted through blood, semen, vaginal fluids, or other body fluids during oral, anal, or genital sex with... read more (particularly due to Chlamydia trachomatis)
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 Ectopic pregnancy is the implantation of a pregnancy in a site other than the endometrial lining of the uterine cavity—ie, in the fallopian tube, uterine cornua, cervix, ovary, or abdominal... read more ).
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 Assisted Reproductive Technologies Assisted reproductive technologies (ARTs) involve manipulation of sperm and ova or embryos in vitro with the goal of producing a pregnancy. For assisted reproductive technologies, oocytes and... read more 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 Pathophysiology reference Ectopic pregnancy is the implantation of a pregnancy in a site other than the endometrial lining of the uterine cavity—ie, in the fallopian tube, uterine cornua, cervix, ovary, or abdominal... read more ).
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 Shock Shock is a state of organ hypoperfusion with resultant cellular dysfunction and death. Mechanisms may involve decreased circulating volume, decreased cardiac output, and vasodilation, sometimes... read more . The later in the pregnancy the rupture occurs, the more rapidly blood is lost and the higher the risk of death.
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
Quantitative serum beta–human chorionic gonadotropin (beta-hCG)
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 Diagnosis reference Ectopic pregnancy is the implantation of a pregnancy in a site other than the endometrial lining of the uterine cavity—ie, in the fallopian tube, uterine cornua, cervix, ovary, or abdominal... read more ).
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 Spontaneous Abortion Spontaneous abortion is pregnancy loss before 20 weeks gestation. Diagnosis is by pelvic examination, measurement of beta subunit of human chorionic gonadotropin, and ultrasonography. Treatment... read more or ectopic pregnancy is likely.
Bleeding Vaginal Bleeding During Early Pregnancy Vaginal bleeding occurs in approximately 20% of confirmed pregnancies during the first 20 weeks of gestation; about half of these cases end in spontaneous abortion ( 1). Vaginal bleeding is... read more is common in early pregnancy (see table for differential diagnosis).
Pelvic pain Pelvic Pain During Early Pregnancy Pelvic pain is common during early pregnancy and may accompany serious or minor disorders. Some conditions causing pelvic pain also cause vaginal bleeding. In some of these disorders (eg, ruptured... read more or pressure is also a common pregnancy symptom (see table for differential diagnosis).
Treatment of Ectopic Pregnancy
Usually, methotrexate for small, unruptured ectopic pregnancies
Surgical resection if rupture is suspected or criteria are not met for methotrexate treatment
Rho(D) immune globulin if the woman is Rh-negative
The American College of Obstetricians and Gynecologists advises that patients with a tubal pregnancy may be treated with methotrexate if none of the following absolute contraindications is present:
Ruptured ectopic pregnancy
Sensitivity to methotrexate
Moderate to severe anemia Evaluation of Anemia Anemia is a decrease in the number of red blood cells (RBCs) as measured by the red cell count, the hematocrit, or the red cell hemoglobin content. In men, anemia is defined as any of the following... read more , leukopenia Overview of Leukopenias Leukopenia is a reduction in the circulating white blood cell (WBC) count to < 4000/mcL (9/L). It is usually the consequence of a reduced number of circulating neutrophils, although... read more , or thrombocytopenia Overview of Platelet Disorders Platelets are circulating cell fragments that function in the clotting system. Thrombopoietin helps control the number of circulating platelets by stimulating the bone marrow to produce megakaryocytes... read more
Clinically important hepatic or renal dysfunction
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
In a commonly used protocol, beta-hCG is measured on day 1, and the patient is given a single dose of methotrexate 50 mg/m2 IM. Beta-hCG measurement is repeated on days 4 and 7. If the beta-hCG level does not decrease by 15% from day 4 to 7, a 2nd dose of 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 Treatment reference Ectopic pregnancy is the implantation of a pregnancy in a site other than the endometrial lining of the uterine cavity—ie, in the fallopian tube, uterine cornua, cervix, ovary, or abdominal... read more ).
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.
Hemodynamically unstable patients require immediate laparotomy and treatment of hemorrhagic shock Treatment of hemorrhagic shock Shock is a state of organ hypoperfusion with resultant cellular dysfunction and death. Mechanisms may involve decreased circulating volume, decreased cardiac output, and vasodilation, sometimes... read more .
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.
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 Ectopic pregnancy is the implantation of a pregnancy in a site other than the endometrial lining of the uterine cavity—ie, in the fallopian tube, uterine cornua, cervix, ovary, or abdominal... read more ).
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.
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.
Treatment usually involves methotrexate, but surgical resection is done if rupture is suspected or criteria are not met for methotrexate treatment.
Drugs Mentioned In This Article
human chorionic gonadotropin
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