INTRODUCTION — Ectopic pregnancy is a pregnancy in which the developing blastocyst becomes implanted at a site other than the endometrium of the uterine cavity. The most common extrauterine location is the fallopian tube, which accounts for 96 percent of all ectopic gestations (picture 1A-B) . Management of these pregnancies has changed dramatically over the years . Preferred management is pharmacologic treatment with methotrexate, rather than surgery. It is important to remember, however, that hemorrhage from ectopic pregnancy is still the leading cause of pregnancy-related maternal mortality in the first trimester and accounts for 4 percent of all pregnancy-related deaths, despite improved diagnostic methods leading to earlier detection and treatment [3,4].
The epidemiology, risk factors, and anatomic sites of ectopic pregnancy will be reviewed here. Related topics regarding ectopic pregnancy are discussed in detail separately, including:
●Clinical manifestations and diagnosis (see "Ectopic pregnancy: Clinical manifestations and diagnosis")
●Choosing a treatment approach (see "Ectopic pregnancy: Choosing a treatment")
●Surgical management (see "Ectopic pregnancy: Surgical treatment")
●Expectant management (see "Ectopic pregnancy: Expectant management")
Incidence — The reported incidence of ectopic pregnancy has varied across time and patient populations. The incidence of ectopic pregnancy is difficult to estimate from available data (hospitalizations, insurance billing records) because inpatient hospital treatment of ectopic pregnancy has decreased and multiple health care visits for a single ectopic pregnancy have increased . Furthermore, since the incidence is expressed as the number of ectopic pregnancies per 1000 pregnancies, the denominator is difficult to determine accurately since early pregnancy failures that do not result in delivery or hospitalization are often not counted.
Representative studies of rates of ectopic pregnancy include:
●A study of a single large health network from 1997 to 2000 showed a rate of 20.7 per 1000 pregnancies .
●A lower rate was reported in a study of over 200 United States commercial health plans from 2002 to 2007, 6.4 per 1000 pregnancies . The incidence increased with age: 15 to 19 years (2.8 per 1000), 20 to 24 (4.4), 25 to 29 (7.4), 35 to 39 (9.9), and 40 to 44 (9.8).
●A study of Medicaid recipients in 14 states from 2004 to 2008 reported a rate of 14.7 per 1000 pregnancies, and data from three states in this study showed a decline in incidence from 2000 to 2008 . Black Americans had a 1.5-fold risk compared with White Americans.
●In a study using data from emergency departments, the incidence of ectopic pregnancy from 2006 to 2013 increased from 11 to 13.7 ectopic pregnancies per 1000 live births and from 7 to 8.3 percent ectopic pregnancy per 1000 pregnancies .
Mortality — In the United States between 1980 and 2007, 876 deaths were attributed to ectopic pregnancy . The ectopic pregnancy maternal mortality ratio declined by 57 percent from 1.15 deaths per 100,000 live births in the period of 1980 to 1984 to 0.50 deaths per 100,000 during 2003 to 2007. A study of Medicaid recipients in 14 states from 2004 to 2008 reported a similar mortality rate, with an ectopic pregnancy mortality ratio of 0.48 per 100,000 live births, although risks of complications were lowest in White patients .
The mortality ratio was 6.8 times higher for African Americans than White Americans and 3.5 times higher for patients older than 35 years than those younger than 25 years during 2003 to 2007 . Of the 76 deaths among patients hospitalized with ectopic pregnancy between 1998 and 2007, 71 percent of the gestations were located in the fallopian tube rather than other sites.
RISK FACTORS — The major cause of ectopic pregnancy is disruption of normal tubal anatomy from factors such as infection, surgery, congenital anomalies, or tumors. Anatomic distortion can be accompanied by functional impairment due to damaged ciliary activity. The highest risk is associated with a history of prior ectopic pregnancy or tubal surgery (table 1) [11,12].
Previous ectopic pregnancy — The risk of repeat ectopic pregnancy in patients with a prior ectopic gestation is approximately three- to eightfold higher compared with other pregnant patients . This risk is related to both the underlying tubal disorder that led to the initial ectopic pregnancy and to the choice of treatment procedure. History of salpingostomy for ectopic pregnancy is a risk factor for recurrent ectopic pregnancy (adjusted odds ratio 3.04) .
Pelvic inflammatory disease and other genital infections — Pelvic infection (eg, nonspecific salpingitis, chlamydia, gonorrhea), especially recurrent infection, is a major cause of tubal pathology and, therefore, increases the risk of ectopic pregnancy. Pelvic infection may alter tubal function and may also cause tubal obstruction and pelvic adhesive disease. Some data suggest that a history of chlamydial infection results in the production of a protein (PROKR2) that makes a pregnancy more likely to implant in the tubes .
The rising incidence of ectopic pregnancy is strongly associated with an increased incidence of pelvic inflammatory disease (PID) . Patients with a history of PID have an approximately threefold increased risk of ectopic pregnancy [12,13].
In a retrospective population-based cohort of patients ages 15 to 44 years in Denmark (1995 to 2012), a positive test for chlamydia was associated with an increase in risk of ectopic pregnancy by 31 percent (adjusted hazard ratio 1.31, 95% CI 1.25-1.38) compared with patients with a negative test . (See "Pelvic inflammatory disease: Pathogenesis, microbiology, and risk factors".)
Pelvic tuberculosis is not commonly associated with ectopic pregnancy. Most patients with pelvic tuberculosis have tubal damage reducing spontaneous conception. Even with in vitro fertilization (IVF), the pregnancy rate is low and the miscarriage rate is high.
Infertility and related factors
Infertility — The incidence of ectopic pregnancy is approximately two- to threefold higher in patients with infertility, although this could reflect the increased incidence of tubal abnormality in this group of patients, which may also be an etiology of infertility [12,13].
In vitro fertilization — IVF has been associated with an increased risk of both tubal ectopic and heterotopic pregnancy . Data from a United States registry of over 550,000 IVF pregnancies found that the rate of ectopic pregnancy declined from 2 percent in 2001 to 1.6 percent in 2011 . This rate is comparable to the ectopic pregnancy rate of 19 per 1000 pregnancies in the general population of the United States . However, study results vary and a multicenter case-control study in China including 2411 patients with ectopic pregnancy matched with other pregnant patients found a 9.3-fold increase in risk with IVF . (See 'Heterotopic pregnancy' below and "In vitro fertilization: Overview of clinical issues and questions".)
In a meta-analysis, day-five embryo transfer was associated with a lower risk of ectopic pregnancy than day-three embryo transfer . In another study of 103,070 IVF cycles that resulted in a clinical pregnancy, 1.38 percent were ectopic pregnancy . The odds of ectopic pregnancy were 65 percent lower in patients who had a frozen compared with a fresh embryo transfer cycles. Perhaps this is related to the use of hormonal stimulation in the fresh cycle .
Cervical, interstitial, and heterotopic pregnancies, in addition to tubal gestations, are encountered more often following IVF. (See 'Cervical pregnancy' below and 'Interstitial or cornual pregnancy' below.)
Tubal reconstructive surgery — Patients with tubal damage or sterilization may undergo tubal reconstructive surgery to attempt to restore tubal fertility, although this has largely been replaced by IVF. The risk of ectopic pregnancy is high after tubal reconstructive surgery, and the outcome depends upon the function and condition of the tube, type of surgery, and surgeon's expertise. Rates of ectopic pregnancy after tubal reconstructive surgery range widely, from 3 to 30 percent . (See "Reproductive surgery for female infertility".)
Other assisted reproduction methods — Several reports have also suggested an association between fertility drugs and ectopic pregnancy, which may be related to altered tubal function secondary to hormonal fluctuation. As an example, in a randomized study, the incidence of ectopic pregnancy was comparable in comparing gonadotropin, clomiphene, or letrozole (7.9, 4.7, and 6 percent, respectively) . However, these rates are higher than that in the general population.
Contraceptive methods — Patients using hormonal contraception or an intrauterine device (IUD) are at very low risk of conceiving any pregnancy, either intrauterine or ectopic. However, if they conceive, the probability of an ectopic pregnancy is generally higher than in those not using contraception .
Sterilization — The risk of ectopic pregnancy in patients who undergo sterilization and then experience sterilization failure is 5- to 19-fold higher than the risk in other pregnant patients. The largest studies include:
●In a study of 44,829 patients undergoing tubal sterilization in Western Australia from 1990 to 2010, 89 had a subsequent ectopic pregnancy for a cumulative probability of 1.7 per 1000 procedures at five years, 2.4 per 1000 by 10 years, and 3 per 1000 by 15 years after surgery . Differences in probability varied by age (highest for younger patients) and by method, though the exact laparoscopic method was unspecified in 40 of the 89 patients with ectopic pregnancy. Bipolar electrosurgery by laparoscopy had a reported risk of ectopic pregnancy of 8.4 per 1000 procedures at both five and 10 years after surgery. For laparoscopic occlusion with the titanium clip (Filshie clip), the probability of ectopic pregnancy was only 1.7 per 1000 procedures at five years and 2 per 1000 at 10 years after sterilization.
●Hysteroscopic sterilization is also associated with an increased risk of ectopic pregnancy, but this risk appears to be lower than with laparoscopic methods. The largest study was based on data from insurance claims in over 27,000 patients and found a 1.3 percent rate of subsequent ectopic pregnancy . (See "Hysteroscopic female permanent contraception", section on 'Pregnancy and outcomes after contraception failure'.)
Intrauterine devices — Patients using an IUD have a lower incidence of ectopic pregnancy than noncontracepting patients because the IUD is a highly effective method of contraception. In one prospective study, rates of ectopic pregnancy (per 1000 woman-years) among those not using contraception, LNG-52 users, and copper IUD users were 6.9, 0.5, and 0.46, respectively .
Among IUD users with contraceptive failure, the risk of ectopic pregnancy is high (1 in 2 pregnancies for the LNG IUD and 1 in 16 pregnancies for the copper IUD versus 1 in 50 pregnancies among noncontraceptors) [29,30]. In a case-control study, the odds of ectopic pregnancy were 16.4-fold higher in patients with current use of an IUD . Rates of contraceptive failure resulting in ectopic pregnancy may be higher among those using the 13.5 mg compared with the 52 mg LNG IUD , but further study is needed.
Estrogen/progestin contraceptives — Similarly, estrogen/progestin oral contraceptives are highly effective and the overall risk of ectopic pregnancy is low, since conception is prevented. However, in patients who do become pregnant while on these contraceptives, the risk of ectopic pregnancy appears to be increased two- to fivefold compared with other pregnant patients .
Progestin-only contraceptives — Progestin-only injection and implant contraceptives are associated with a low incidence of ectopic pregnancy. In one retrospective study including contraceptive users, the incidence of ectopic pregnancy (in woman-years) for users of depot medroxyprogesterone acetate, implant contraceptives, and progestin-only pills was 1.8, 2, and 15.2, respectively .
Smoking — Cigarette smoking in the periconceptional period is associated with an increased risk of ectopic pregnancy [12,33]. A history of smoking is associated with a two- to threefold increase in ectopic pregnancy risk and current use is associate with a two- to fourfold risk; the risk may be dose-dependent.
A possible explanation for this finding may be impaired in tubal motility in smokers or impaired immunity, thus predisposing them to pelvic inflammatory disease.
In utero DES exposure — Patients with a history of in utero diethylstilbestrol (DES) exposure have a fourfold increased risk of ectopic pregnancy due to abnormal tubal morphology and, possibly, impaired fimbrial function. There was a 3.7-fold increase risk associated with DES exposure compared with no exposure . (See "Outcome and follow-up of diethylstilbestrol (DES) exposed individuals", section on 'Ectopic pregnancy'.)
Vaginal douching — Regular vaginal douching is associated with an up to threefold increased risk of ectopic pregnancy .
Increasing age — There is an increasing proportion of ectopic pregnancies among patients in the older age groups . In a study at a large health network, during 1997 to 2000, ectopic pregnancy rates among those ages 15 to 19, 20 to 29, 30 to 39, and 40 to 49 years were 12.5 per 1000 females, 16.6, 25.3, and 42.5, respectively . This high incidence in older patients may be a reflection of cumulative risk factors over time.
Endometriosis — Endometriosis may be associated with ectopic pregnancy. In a meta-analysis including 15 cohort and case-control studies, endometriosis was associated with an increased risk of ectopic pregnancy (odds ratio [OR] 2.16 to 2.66, 95% CI 1.67-2.79 and 1.14-6.21); however, there was high heterogeneity among studies .
Other — Other factors, such as blood pressure, body mass index, low density lipoprotein cholesterol, and alcohol consumption do not appear to be associated with an increased risk of ectopic pregnancy .
ANATOMIC SITES — The great majority of ectopic pregnancies implant in the fallopian tube (96 percent). In one series of 1800 surgically treated cases, the distribution of sites was ampullary (70 percent), isthmic (12 percent), fimbrial (11.1 percent), ovarian (3.2 percent), interstitial (2.4 percent), and abdominal (1.3 percent) .
Tubal pregnancy — Several factors may be involved in the pathogenesis of tubal pregnancies, but they are generally believed to be the result of (1) conditions that delay or prevent passage of the fertilized oocyte into the uterine cavity or (2) factors inherent in the embryo that result in premature implantation.
Pathogenesis — Studies of tubal pregnancy have detected several factors that may impact blastocyst implantation.
•Chronic salpingitis – Tubal pathology, particularly chronic salpingitis, is observed in up to 90 percent of surgical specimens of tubal pregnancies. Chronic salpingitis is six times more common in tubes containing an ectopic pregnancy than in normal tubes . The histologic features of chronic salpingitis are attenuation and blunting of the plicae and infiltration of the tubal wall by plasma cells and lymphocytes. In a study of 231 patients with ectopic pregnancy, transvaginal sonography showed an adnexal abnormality in nearly 95 percent of the patients, most commonly a nonspecific adnexal mass .
•Salpingitis isthmica nodosa – Salpingitis isthmica nodosa is noted in approximately 10 percent of patients with a tubal pregnancy. The gross appearance of salpingitis isthmica nodosa is bilateral nodularities in the isthmic portion of the tube. Histologically, the tubal mucosa penetrates into the myosalpinx, leading to hypertrophy of the surrounding muscular layers. The etiology of salpingitis isthmica nodosa is not known.
•The depth of implantation of the gestational sac varies according to the location of the ectopic pregnancy within the fallopian tube. A histopathologic study of 84 tubal pregnancies found that the gestational sac was inside the tubal lumen in one-half of ampullary pregnancies . The muscularis of the tube was preserved in most of these cases. By comparison, the gestational sac was usually detected extraluminally or both inside and outside the lumen in isthmic pregnancies and the disruption of the tubal wall was more extensive. This suggests that the trophoblast penetrates the tubal wall relatively early in isthmic pregnancy.
●Serum or extracellular factors – A number of factors (eg, lectin, integrin, matrix-degrading cumulus, prostaglandins, growth factors, cytokines, and modulator proteins ) may cause premature implantation in the tube.
●Embryonic factors – Embryonic cardiac activity was seen in fewer than 10 percent of tubal gestations in one study . Fetal chromosomal and anatomic abnormalities have been found as well. However, chromosomal abnormality is probably not an important etiology of ectopic pregnancy .
Interstitial or cornual pregnancy — The interstitial portion of the fallopian tube is the proximal segment that is embedded within the muscular wall of the uterus. A pregnancy implanted at this site is called an interstitial pregnancy (figure 1); the term cornual pregnancy is also widely used to describe a pregnancy at this location. Originally, the term cornual pregnancy referred only to pregnancies implanted in either the horn of a bicornuate uterus, a rudimentary horn of a unicornuate uterus, or in the lateral half of a septated or partially septated uterus .
Interstitial pregnancies may be misdiagnosed as intrauterine because they are partially implanted in the endometrium. A clue to correct diagnosis is its eccentric location and thin (less than 5 mm) myometrial mantle. Contrary to previous belief, rupture of interstitial pregnancy occurs relatively early in pregnancy . (See "Ultrasonography of pregnancy of unknown location", section on 'Interstitial pregnancy'.)
These pregnancies are uncommon, comprising approximately 1 to 3 percent of all ectopic pregnancies [43,45,46]. The risk factors are similar to those for other tubal pregnancies, except for ipsilateral salpingectomy, which is a risk factor that is specific to interstitial pregnancy. Related topics regarding the treatment of interstitial pregnancy are discussed in detail elsewhere. (See "Ectopic pregnancy: Methotrexate therapy", section on 'Patients with an interstitial pregnancy: Multiple-dose' and "Ectopic pregnancy: Surgical treatment", section on 'Interstitial pregnancy'.)
The following types of pregnancies are intrauterine pregnancies but are often mistaken for an interstitial pregnancy:
●Rudimentary uterine horn pregnancy – A rudimentary horn pregnancy is an intrauterine pregnancy that is located in the rudimentary uterine horn of a unicornuate uterus. The term "cornual pregnancy" was originally used to refer exclusively to either this location of a gestation or one located in the horn of a bicornuate uterus, as noted above. However, such pregnancies have a high risk of uterine rupture. This is discussed in detail separately. (See "Congenital uterine anomalies: Clinical manifestations and diagnosis".)
●Angular pregnancy – Angular pregnancy is an intrauterine pregnancy with a clinical course distinct from interstitial pregnancy . The pregnancy is implanted medial to the uterotubal junction in the lateral angle of the uterine cavity, close to the proximal ostium of the fallopian tube. In contrast with an interstitial pregnancy, an angular pregnancy is located medial to the round ligament . Additional criteria to help better define an angular pregnancy are presented in the table (table 2) .
When viewed from the exterior of the uterus during laparoscopy or laparotomy, the uterine enlargement caused by an angular pregnancy displaces the round ligament superiorly and laterally, while remaining medial to the ligament itself. On the other hand, an interstitial pregnancy causes an enlargement of the uterus that is lateral to the round ligament.
Angular pregnancy appears to be rare, and there are few reports regarding its diagnosis or management. Uterine rupture has rarely been reported with this type of pregnancy . In a case series of 42 patients with angular pregnancies followed clinically, 80 percent resulted in live births, 20 percent resulted in early pregnancy loss, and there were no cases of uterine rupture or major morbidity .
Abdominal pregnancy — An abdominal pregnancy is a rare form of ectopic pregnancy that may be primary, resulting from direct implantation of the blastocyst on the peritoneal surface or abdominal viscera, or secondary, resulting from extrusion of an embryo from the tube. This is discussed in detail separately. (See "Abdominal pregnancy".)
Cervical pregnancy — A cervical pregnancy is a rare form of ectopic pregnancy in which the trophoblast implants in the cervical tissue of the endocervical canal. (See "Cervical pregnancy".)
Cesarean scar pregnancy — A pregnancy may implant in the uterus but at a depth or location that may result in life-threatening hemorrhage and rupture of the uterine wall [49-53].
Cesarean scar pregnancy (CSP) is a pregnancy located in or on the scar of a prior cesarean birth. Pregnancies implanted on or in myomectomy scars (also referred to as intramural pregnancy) can also occur. This is discussed in detail separately. (See "Cesarean scar pregnancy".)
Heterotopic pregnancy — Heterotopic pregnancy refers to the combination of an intrauterine pregnancy and a concurrent pregnancy at an ectopic location. While heterotopic pregnancy used to be rare (estimated to occur in 1 in 30,000 pregnancies ), with the emergence of assisted reproductive technology (ART; including super-ovulation, intrauterine insemination, and in vitro fertilization), the overall incidence of heterotopic pregnancy has been increasing [55-57]. An analysis of all registered ART pregnancies in the United States from 1999 to 2002 reported an incidence of 1.5 per 1000 ART pregnancies .
The increased incidence of heterotopic pregnancies in those receiving ART may be related to the high rates of tubal disease, high levels of estradiol and progesterone, or high numbers of transferred embryos or ovulated oocytes in this population [55,58,59]. Other factors, such as volume and viscosity of transfer medium and the technique of embryo transfer, may also play a role .
Ovarian pregnancy — Ovarian pregnancy occurs in 1 per 2100 to 1 per 60,000 pregnancies or approximately 1 to 3 percent of ectopic pregnancies and is becoming more common . In contrast with tubal pregnancy, a history of pelvic inflammatory disease or the use of an intrauterine contraceptive device does not increase the risk of ovarian pregnancy. Ovarian pregnancy appears to be a random event that is not associated with a history of infertility or recurrent extrauterine pregnancy.
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".)
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 5th to 6th 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 10th to 12th 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 topic (see "Patient education: Ectopic pregnancy (The Basics)")
●Beyond the Basics topic (see "Patient education: Ectopic (tubal) pregnancy (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition – Ectopic pregnancy is a pregnancy in which the developing blastocyst becomes implanted at a site other than the endometrium of the uterine cavity. (See 'Introduction' above.)
●Epidemiology – The incidence of ectopic pregnancy is difficult to estimate and varies across time and patient populations; representative studies report rates from 6.4 to 20.7 per 1000 pregnancies. (See 'Incidence' above.)
●Morbidity and mortality – Ectopic pregnancy is a major cause of maternal morbidity and mortality. Hemorrhage from ectopic pregnancy is the leading cause of maternal mortality in the first trimester and accounts for 4 to 10 percent of all pregnancy-related deaths. (See 'Introduction' above and 'Mortality' above.)
•Risk factors for ectopic pregnancy include previous ectopic pregnancy, pelvic inflammatory disease, smoking, and in vitro fertilization. Other risk factors are listed in the table (table 1). (See 'Risk factors' above.)
•The absolute risk of ectopic pregnancy in patients using contraception or sterilization is low since pregnancy is prevented. However, if contraceptive or sterilization failure occurs, the risk of ectopic pregnancy is higher than in noncontracepting patients. (See 'Sterilization' above and 'Contraceptive methods' above.)
●Anatomic sites – The most common location of an ectopic pregnancy is the fallopian tube, but ectopic pregnancies also occur in the cervix, ovary, hysterotomy scar, and abdomen, as well as in combination with an intrauterine pregnancy (heterotopic pregnancy). (See 'Anatomic sites' above.)