CHAPTER 7: Ectopic Pregnancy

An ectopic or extrauterine pregnancy is one in which the blastocyst implants anywhere other than the endometrial lining of the uterine cavity. Nearly 95 percent of ectopic pregnancies implant in the fallopian tube. Other sites are shown in Figure 7-1, which reflects data from 1800 surgically treated ectopic pregnancies (Bouyer, 2002). Bilateral ectopic pregnancies are rare, and their estimated prevalence is 1 of every 200,000 pregnancies (al-Awwad, 1999).

Reported incidences rates of ectopic pregnancy are less reliable than in the past as outpatient treatment protocols render national hospital discharge statistics invalid. One estimate by Kaiser Permanente of North California was 2.07 percent of total pregnancies from 1997 to 2000 (Van Den Eeden, 2005). Hoover and colleagues (2010) queried a large claims database of privately insured women between 2002 and 2007 and calculated a rate of 0.64 percent. However, this may not accurately reflect the cases in higher-risk, lower-socioeconomic, uninsured populations. Stulberg and coworkers (2014) reviewed 2004 to 2008 Medicaid claims data from 14 states. They reported a rate of 1.4 percent and noted that black women were 46 percent more likely to experience an ectopic pregnancy than whites in this government-insured group.

Among several factors that help explain the incidence of ectopic pregnancies are: (1) greater sexually transmitted disease prevalence, (2) diagnostic tools with improved sensitivity, (3) tubal factor infertility, (4) delayed childbearing and accompanied use of assisted reproductive technology, and (5) increased intrauterine device (IUD) use and tubal sterilization, which predispose to ectopic pregnancy if the method fails (Ankum, 1996; Li, 2014a; Ljubin-Sternak, 2014).

Ectopic pregnancy remains the leading cause of early pregnancy-related death. Still, current diagnostic and treatment protocols have resulted in substantial declines in fatality rates. One analysis showed a 56-percent decline in the ectopic pregnancy mortality ratio between the 1980 to 1984 epoch and the 2003 to 2007 epoch. During this later span, African-American women were approximately three times more likely to die as a result of ectopic pregnancy complications than whites (Creanga, 2011). Inadequate access to gynecologic and prenatal care may partially explain this trend.

In most of these cases, death is directly related to severe hemorrhage from tubal rupture. Risk factors that increase the likelihood of tubal rupture include ovulation induction, serum β-human chorionic gonadotropin (β-hCG) level >10,000 IU/L, and never having used contraception (Job-Spira, 1999). Appreciation of these characteristics can aid prompt surgical intervention.

Several risks have been linked with ectopic pregnancy (Table 7-1). Among these, documented tubal pathology, surgery to restore tubal patency, or tubal sterilization can all lead to obstruction and subsequent ectopic pregnancy. A woman with two prior ectopic pregnancies has a 10- to 16-fold increased chance for another (Barnhart, 2006; Skjeldestad, 1998).

Smoking, which may be a surrogate marker for sexually transmitted infections, increases the ectopic pregnancy risk three- to fourfold in women who smoke more than one pack of cigarettes daily (Saraiya, 1998). The increased risk of ectopic pregnancy among smokers undergoing assisted reproductive technology was verified in a metaanalysis by Waylen and associates (2009). In addition, animal studies show that smoking alters oocyte cumulus complex pick-up and embryo transport through its effects on ciliary function and smooth-muscle contraction (Shaw, 2010; Talbot, 2005).

Assisted reproductive technology (ART) for sub- or infertile couples has a 0.8-percent incidence of ectopic pregnancy per transfer and 2.2 percent per clinical pregnancy (Coste, 2000). Interestingly, recent series note significant reductions in ectopic pregnancy rates at the time of in vitro fertilization (IVF) if frozen-thawed embryos (2.2 percent rate) are used rather than those from fresh cycles (4.6 percent) (Fang, 2015; Huang, 2014). In women undergoing IVF, the main risk factors for ectopic pregnancy are tubal factor infertility and hydrosalpinges (Strandell, 1999; Van Voorhis, 2006). Moreover, “atypical” implantation—that is, interstitial, abdominal, cervical, ovarian, or heterotopic—is more common following ART procedures. As a review, heterotopic pregnancy is an intrauterine pregnancy coexistent with an extrauterine pregnancy.

Older reproductive-aged women, specifically women aged 35 to 44 years, carry a threefold risk of ectopic pregnancy compared with those aged 15 to 25 years (Goldner, 1993). These have been attributed to age-related hormonal changes that alter tubal function (Coste, 2000).

Contraception lowers overall pregnancy rates and thereby lowers ectopic pregnancy rates. However, if pregnancy does occur, some methods increase the relative incidence of ectopic pregnancy. Examples include the levonorgestrel-releasing intrauterine system (Mirena) and copper IUD (ParaGard). In one study of 61,448 IUD users, 118 contraceptive failures were reported, and 21 of these were ectopic (Heinemann, 2015). Progestin-only contraceptive pills also pose a slightly increased risk because of their effects to diminish tubal motility. With tubal sterilization failure, ectopic pregnancy is a concern. In one study, this risk was 3.5 times greater in women younger than 28 years at the time of sterilization. This may be in part because of age-related fecundity. Of methods, higher ectopic rates were noted with laparoscopic partial salpingectomy and electrodestruction methods (Malacova, 2014).

Acute inflammation has been implicated in the tubal damage that predisposes to ectopic pregnancies. Chronic salpingitis and salpingitis isthmica nodosa also contribute (Kutluay, 1994).

Of suspected agents, recurrent chlamydial infection causes intraluminal inflammation, subsequent fibrin deposition, and tubal scarring (Hillis, 1997). Moreover, persistent chlamydial antigens can trigger a delayed hypersensitivity reaction that promotes continued scarring despite negative culture results (Toth, 2000). Whereas endotoxin-producing Neisseria gonorrhoeae causes virulent pelvic inflammation that has a rapid clinical onset, the chlamydial inflammatory response is chronic and peaks at 7 to 14 days.

Inflammation within the fallopian tube can also arrest embryo progress and provide a premature proimplantation signal (Shaw, 2010). Specifically, oviduct interstitial cells of Cajal are specialized pacemaker cells responsible for oviduct motility and egg transport. Infections in mice by Chlamydia muridarum, which is similar to human Chlamydia trachomatis, lead to absent spontaneous pacemaker activity and may offer another explanation of how chlamydial infection increases ectopic pregnancy rates in humans (Dixon, 2009).

Another factor involved with oviductal transport of embryos is the cannabinoid receptor (CB1), which is mediated by endocannabinoid signaling. Chronic exposure to nicotine can affect endocannabinoid levels and lead to fallopian tube dysfunction (Horne, 2008).

The mechanism for ectopic pregnancy in women using ART has been a conundrum because the fallopian tube is typically bypassed. Revel and colleagues (2008) sought to establish the relationship between E-cadherin, an adhesion molecule, and tubal ectopic pregnancy implantation sites. They found E-cadherin strongly localized to the tubal embryo implantation site only in women who underwent IVF. This suggests a biologic rather than mechanical factor accounting for the ectopic pregnancies associated with IVF.

Once normal tubal transport has been disrupted, fallopian tube anatomy plays an important role in tubal pregnancy genesis. Namely, the fallopian tube lacks a submucosal layer beneath its epithelium. Therefore, a fertilized ovum can easily burrow through the epithelium and implant within tube’s muscularis layer (Fig. 7-2). As rapidly proliferating trophoblasts erode the muscularis layer, maternal blood pours into the spaces within the trophoblastic or the adjacent tissue.

With this process, the location of a tubal pregnancy may predict the extent of damage. Senterman and associates (1988) studied histologic samples from 84 isthmic and ampullary pregnancies. They reported that half of the ampullary pregnancies were intraluminal, and the muscularis was preserved in 85 percent of these. Conversely, isthmic gestations were found both intra- and extraluminally with greater disruption of the tubal wall. The timing of tubal rupture is also partially dependent on pregnancy location. As a rule, fallopian tubes rupture earlier if implantation is in the isthmic or ampullary portion. Later rupture is seen if the ovum implants within the interstitial portion. Rupture is usually spontaneous but can also follow trauma such as that associated with bimanual pelvic examination or coitus.

After implantation, differences in ectopic pregnancy develop­ment explain the typically divergent clinical paths between acute and chronic ectopic pregnancies. Acute ectopic pregnancies are those with a high serum β-hCG level at presentation. These high β-hCG levels correlate with the depth of trophoblastic invasion into the tubal wall. Greater invasion promotes concomitant severe ischemic changes and tubal wall rupture (Erol, 2015). Rapid pregnancy growth leads to an immediate diagnosis from painful tubal distention or from rupture. Indeed, these carry a higher risk of tubal rupture compared with chronic ectopic pregnancies (Barnhart, 2003c).

With chronic ectopic pregnancy, minor repeated ruptures or tubal abortion incites an inflammatory response that leads to formation of a pelvic mass. Its abnormal trophoblasts die early. Thus, negative or lower, static serum β-hCG levels are found. Chronic ectopic pregnancies typically rupture late, if at all, but commonly form a complex pelvic mass. In these cases, it often is the mass, rather than pain or bleeding, that prompts diagnostic surgery (Cole, 1982; Uğur, 1996).

The classic symptom triad of ectopic pregnancy is amenorrhea followed by vaginal bleeding and ipsilateral abdominal pain. However, as women seek care earlier, the ability to diagnose ectopic pregnancy before rupture—even before the onset of symptoms—is not unusual. Of other symptoms, banal pregnancy discomforts such as breast tenderness, nausea, and urinary frequency may accompany more ominous findings. These include shoulder pain worsened by inspiration, which is caused by phrenic nerve irritation from subdiaphragmatic blood, or vasomotor disturbances such as vertigo and syncope from hemorrhagic hypovolemia.

Of physical findings, some women have orthostatic findings from hypovolemia. Birkhahn and associates (2003) employed the shock index to evaluate the severity of ruptured ectopic pregnancy. This index is the heart rate divided by systolic blood pressure and can assess trauma patients for hypovolemic or septic shock. The normal range lies between 0.5 and 0.7 for nonpregnant patients. A shock index >0.85 and a systolic blood pressure <110 mm Hg are highly suggestive of a potentially life-threatening gynecologic emergency, such as a ruptured ectopic pregnancy (Birkhahn, 2003; Polena, 2015). Despite these findings of advanced hypovolemia, normal vital signs are unreliable to exclude earlier stages of tubal rupture.

Abdominal and pelvic findings may also be notoriously scarce in many women before tubal rupture. With rupture, however, nearly three fourths will have marked tenderness on both abdominal and pelvic examination, and pain is aggravated with cervical manipulation. A pelvic mass, including fullness posterolateral to the uterus, can be palpated in approximately 20 percent of women. Initially, an ectopic pregnancy may feel soft and elastic, whereas extensive intraluminal hemorrhage produces a firmer consistency. Many times, discomfort precludes palpation of the mass, and limiting examinations may help avert iatrogenic rupture.

Symptoms of ectopic pregnancy can mimic multiple entities (Table 7-2). Early pregnancy complications such as threatened or missed abortion or hemorrhagic corpus luteum cyst may be difficult to differentiate. Moreover, approximately 20 percent of women with normal pregnancies have early bleeding. Several disorders not related to pregnancy can also mimic ectopic pregnancy. In general, a positive test for β-hCG usually excludes these other diagnoses. However, these conditions may exist concurrently with pregnancy—either intrauterine or ectopic. Transvaginal sonography and serial serum β-hCG measurements are the most valuable diagnostic aids to confirm clinical suspicions of an ectopic pregnancy. Additionally, because ectopic pregnancy can lead to significant bleeding, a hemogram is an additional fast and effective initial screen.

Laboratory Findings

Serum β-hCG Measurements

Human chorionic gonadotropin is a glycoprotein produced by syncytiotrophoblast and can be detected in serum as early as 8 days after the luteinizing hormone (LH) surge. In normal pregnancies, serum β-hCG levels rise in a log-linear fashion until 60 or 80 days after the last menses, at which time values plateau at approximately 100,000 IU/L. Given an interassay variability of 5 to 10 percent, interpretation of serial values is more reliable when performed by the same laboratory.

With a robust intrauterine pregnancy (IUP), serum β-hCG levels should increase at least 53 to 66 percent every 48 hours (Barnhart, 2004; Kadar, 1982). Seeber and associates (2006) used an even more conservative 35-percent rise after 48-hours. Past this 48 hours, allowing time for additional data may better determine the location and viability of the pregnancy. But, this is weighed against the increased chance of ectopic pregnancy rupture during these extra diagnostic days. In hemodynamically stable women, adding a third serum β-hCG level on day 4 or 7 could correct the diagnosis of a pregnancy of unknown location in an additional 7 to 13 percent of patients (Zee, 2013). Nevertheless, inadequately rising serum β-hCG levels indicate only a dying pregnancy, not its location.

Many women present with an unsure last menstrual period, and an educated guess of gestational age is made. In these cases, correlation between the serum β-hCG concentration and transvaginal sonography findings becomes especially important.

Serum Progesterone Levels

Serum progesterone concentration is used by some to aid ectopic pregnancy diagnosis when serum β-hCG levels and sonographic findings are inconclusive (Stovall, 1992). Serum progesterone concentration varies minimally between 5 and 10 weeks’ gestation, thus a single value is sufficient. Mol and coworkers (1998) performed a metaanalysis of 22 studies to assess the accuracy of a single serum progesterone level to differentiate ectopic from uterine pregnancy. They found that results were most accurate when approached from the viewpoint of healthy versus dying pregnancy. With serum progesterone levels <5 ng/mL, a dying pregnancy was detected with near perfect specificity and with a sensitivity of 60 percent. Conversely, values of >20 ng/mL had a sensitivity of 95 percent with specificity approximating 40 percent to identify a healthy pregnancy. Ultimately, serum progesterone levels can be used to buttress a clinical impression, but again they cannot reliably differentiate between an ectopic and intrauterine pregnancy (Guha, 2014).

Sonography

High-resolution sonography has revolutionized the clinical management of women with a suspected ectopic pregnancy. With transvaginal sonography (TVS), a gestational sac is usually visible between 4½ and 5 weeks, the yolk sac appears between 5 and 6 weeks, and a fetal pole with cardiac activity is first detected at 5½ to 6 weeks. With transabdominal sonography, these structures are visualized slightly later. The sonographic diagnosis of ectopic pregnancy rests on visualization of an adnexal mass separate from the ovary (Fig. 7-3).

When the last menstrual period is unknown, serum β-hCG testing is used to define expected sonographic findings. Each institution must define a β-hCG discriminatory value for TVS, that is, the lower limit at which an examiner can reliably visualize an IUP. At most institutions, this value is a concentration between 1500 and 2000 IU/L. Accurate diagnosis by sonography is three times more likely if the initial β-hCG level is above this value. Connolly and colleagues (2013) reported evidence to suggest an even higher threshold. They noted that with live IUPs, a gestational sac was seen 99 percent of the time with a discriminatory level of 3510 IU/L. Even with β-hCG levels above the chosen discriminatory value, technical challenges such as leiomyomas, adenomyosis, multifetal gestation, or IUD can hinder the ability to accurately diagnose an intrauterine gestation (Gurel, 2007; Ko, 2014).

When β-hCG levels are above the set discriminatory value, the absence of an IUP may suggest an abnormal pregnancy. The abnormality may be an ectopic pregnancy, an incomplete abortion, or a resolving completed abortion. For example, despite total passage of products of conception with complete abortion, β-hCG testing may still be positive while original β-hCG is metabolized and cleared. Conversely, when β-hCG values lie below the discriminatory value, sonographic findings are not diagnostic in nearly two thirds of cases (Barnhart, 1999).

In an attempt to unify the language used with sonographic evaluation of early pregnancies, a consensus statement was drafted with five categories: (1) definitive ectopic pregnancy (extrauterine gestational sac with yolk sac and/or embryo), (2) probable ectopic pregnancy (inhomogeneous adnexal mass or extrauterine sac-like structure), (3) probable IUP (intrauterine echogenic sac), (4) definite IUP (intrauterine gestational sac with yolk sac and/or embryo), and (5) pregnancy of unknown location (PUL) (lacking signs of either ectopic pregnancy or IUP) (Barnhart, 2011).

Systematic sonographic evaluation is critical to establish the correct diagnosis. Most begin with the endometrial cavity. In pregnancies conceived spontaneously, identification of an IUP effectively excludes the possibility of ectopic implantation. When ART is employed, however, careful examination of the tube and ovary is performed even with an intrauterine pregnancy because heterotopic pregnancy rates may be as high as 1 per 100 (Tal, 1996). An intracavitary fluid collection caused by bleeding from the decidua can create a pseudogestational sac, or pseudosac. As shown in Figure 7-4, this one-layer collection lies typically in the midline of the uterine cavity. In contrast, a normal gestational sac is eccentrically located (Dashefsky, 1988). Another intracavitary finding is a trilaminar endometrial pattern, which represents two adjacent proliferative-phase endometrial layers (Fig. 2-16) (Lavie, 1996). For the diagnosis of ectopic pregnancy, this finding’s specificity is 94 percent but with a sensitivity of only 38 percent (Hammoud, 2005). Endometrial stripe thickness has not been well correlated with ectopic pregnancies. However, Moschos and Twickler (2008b) determined that in PULs, none that ultimately proved to be normal IUPs had a stripe thickness <8 mm.

The fallopian tubes and ovaries are also inspected. Visualization of an extrauterine yolk sac or embryo clearly confirms an ectopic pregnancy, although such findings are less commonly seen (Paul, 2000). In some cases, a halo or tubal ring that surrounds an anechoic sac can be seen. According to Burry and associates (1993), this has a positive-predictive value of 92 percent and a sensitivity of 95 percent. Alternatively, an inhomogeneous complex adnexal mass is usually caused by hemorrhage within the ectopic sac or by an ectopic pregnancy that has ruptured into the tube. Overall, approximately 60 percent of ectopic pregnancies are seen as an inhomogeneous mass adjacent to the ovary; 20 percent appear as a hyperechoic ring; and 13 percent have an obvious gestational sac with a fetal pole (Condous, 2005). Brown and associates (1994) conducted a metaanalysis of 10 studies to ascertain the best transvaginal sonographic criteria to diagnose ectopic pregnancy. They reported that the finding of any adnexal mass, other than a simple ovarian cyst, was the most accurate. With this, they found a sensitivity of 84 percent, specificity of 99 percent, positive-predictive value of 96 percent, and negative-predictive value of 95 percent. However, not all adnexal masses represent an ectopic pregnancy, and integration of sonographic findings with other clinical information is necessary.

Differentiating an ectopic pregnancy from a corpus luteum cyst can be challenging. However, Swire and coworkers (2004) observed that the corpus luteum wall is less echogenic ­compared with both a tubal ring and the endometrium. They found that a spongelike, lacelike, or reticular pattern seen within the cyst is classic for hemorrhage (Fig. 9-16). Moreover, a corpus luteum is found within the parenchyma of an ovary, but a markedly asymmetric appearing ovary should raise suspicion of an ectopic pregnancy (Gurel, 2007). With transvaginal color Doppler imaging, placental blood flow within the periphery of the ectopic pregnancy—the ring of fire—can be seen (Fig. 7-5). Although this finding can aid ectopic pregnancy diagnosis, a ring of fire also can be seen with a corpus luteum of pregnancy (Pellerito, 1992). Pulsed-color Doppler sonographic measurement of resistance indices has poor sensitivity and limits its utility (Atri, 2003). Finally, to help characterize a suspicious mass, an examiner can gently palpate an adnexum that is placed between the vaginal probe and the examiner’s abdominal hand during real-time scanning. A mass that moves separately from the ovary suggests a tubal pregnancy, whereas a mass that moves synchronously more likely represents a corpus luteum cyst (Levine, 2007).

During sonographic evaluation of the pelvis, TVS can detect as little as 50 mL of free peritoneal fluid in the cul-de-sac of Douglas. This may be intraabdominal bleeding or physiologic peritoneal fluid. A large volume of fluid or fluid that is echogenic is more worrisome for hemoperitoneum. In addition, transabdominal right-upper-quadrant sonographic imaging helps assess the extent of hemoperitoneum. Blood in the paracolic gutters and Morison pouch indicates significant hemorrhage. Specifically, free fluid in Morison pouch typically is not seen until a hemoperitoneum reaches 400 to 700 mL (Branney, 1995; Rodgerson, 2001). Detection of peritoneal fluid in conjunction with an adnexal mass is highly predictive of ectopic pregnancy (Nyberg, 1991). That said, despite technologic advances, the absence of suggestive findings does not exclude ectopic pregnancy.

Culdocentesis

With a 16- to 18-gauge spinal needle, the cul-de-sac of Douglas may be entered through the posterior vaginal fornix (Fig. 7-6). The aspirate characteristics, in conjunction with clinical findings, may help clarify the diagnosis. Normal-appearing peritoneal fluid is designated as a negative test. If fragments of an old clot or nonclotting blood are found in the aspirate when placed into a dry, clean test tube, then hemoperitoneum is diagnosed. If the aspirated blood clots after it is withdrawn, this may signify active intraperitoneal bleeding or puncture of an adjacent vessel. If fluid cannot be aspirated, the test can only be interpreted as unsatisfactory. Purulent fluid suggests an infection-related cause such as salpingitis or appendicitis. Feculent material may originate from a perforated colon or an inadvertent puncture of the rectosigmoid colon during culdocentesis.

Several studies have challenged the usefulness of this ­bedside test, and culdocentesis has been largely replaced by TVS (Glezerman, 1992; Vermesh, 1990). Sonography with findings of echogenic fluid to establish hemoperitoneum is more sensitive and specific than culdocentesis—100 and 100 percent versus 66 and 80 percent, respectively. Also, for most women, sonography is better tolerated.

Endometrial Evidence

Several endometrial changes are associated with ectopic pregnancy. These include decidua found in 42 percent of samples, secretory endometrium in 22 percent, and proliferative endometrium in 12 percent, all with an absence of trophoblasts (Lopez, 1994). Decidua is endometrium that is hormonally prepared for pregnancy, and the degree to which the endometrium is converted with ectopic pregnancy is variable. Thus, in addition to bleeding, women with ectopic tubal pregnancy may pass a decidual cast, which is the entire sloughed endometrium that reflects the form of the endometrial cavity (Fig. 7-7). Decidual sloughing may also occur with IUP abortion. Thus, tissue is carefully evaluated visually and then histologically for evidence of a conceptus. If no clear gestational sac is visually seen or if no villi are identified histologically within the cast, then the possibility of ectopic pregnancy must still be entertained.

Before methotrexate treatment is given for ectopic pregnancy treatment, many recommend that the absence of intrauterine trophoblastic tissue be confirmed by curettage (Barnhart, 2002; Chung, 2011; Shaunik, 2011). The presumptive diagnosis of ectopic pregnancy is inaccurate in nearly 40 percent of cases without histologic exclusion of a spontaneous pregnancy loss. Nevertheless, the need, method, and risks of endometrial sampling must carefully be weighed against the limited risks of methotrexate.

Endometrial biopsy with a Pipelle catheter was studied as an alternative to curettage and found inferior. The sensitivity of obtaining chorionic villi ranged from 30 to 63 percent (Barnhart, 2003b; Ries, 2000). By comparison, frozen section of curettage fragments to identify products of conception is accurate in more than 90 percent of cases (Barak, 2005; Li, 2014b; Spandorfer, 1996).

Summary of Diagnostic Evaluation

Confirmation by diagnostic laparoscopy remains the gold standard for ectopic pregnancy diagnosis (Fig. 7-8). That said, with sensitive diagnostic modalities available, ectopic pregnancy can typically be diagnosed prior to surgery, and use of an evidence-based algorithm can assist. After appropriate clinical evaluation, all reproductive-aged women with any suspicion of pregnancy are tested using a sensitive urine β-hCG assay. Following positive testing, if an IUP is not confirmed by sonography, if no signs of acute intraabdominal hemorrhage are present, and if an ectopic gestation is suspected, then an evaluation such as the one depicted in Figure 7-9 may be used. Gracia and Barnhart (2001) performed a decision analysis of six diagnostic strategies to evaluate which sequence of tests was most efficient in missing the fewest ectopic pregnancies and interrupting the fewest IUPs. They found the best strategy was to include TVS for all women with first-trimester pain or bleeding. If findings are not diagnostic, then serial serum β-hCG levels are measured. Using this strategy, only 1 percent of all potential IUPs were interrupted; no ectopic pregnancies were missed; and the average time to diagnosis was 1.46 days.

Without intervention, an ectopic tubal pregnancy can lead to tubal abortion, tubal rupture, or spontaneous resolution. Tubal abortion is the expulsion of products through the fimbrial end. This tissue can then either regress or reimplant in the abdominal cavity. With reimplantation, bleeding or pain necessitating surgical intervention is a common complication. Tubal rupture is associated with significant intraabdominal hemorrhage. With spontaneous resolution, small ectopic pregnancies die and are resorbed without adverse patient effects. As with the ending of any early pregnancy, Rh status is assessed. If a woman is D negative and her partner has a blood group that is either D positive or unknown, then 300 μg anti-D immune globulin is given to prevent anti-D isoimmunization.

Medical Management

Medical therapy is preferred for most ectopic pregnancies, if feasible. Only methotrexate has been extensively studied as an alternative to surgical therapy. The best candidate for medical therapy is a woman who is asymptomatic and motivated and who has resources to be compliant with surveillance. Absolute contraindications for medical therapy with methotrexate include hemodynamic instability and those shown in Table 7-3 (American College of Obstetricians and Gynecologists, 2014; American Society for Reproductive Medicine, 2013). With medical therapy, some classic predictors of success are the initial serum β-hCG level, ectopic pregnancy size, and fetal cardiac activity.

Of these, the β-hCG level is the single best prognostic indicator of treatment success in women given single-dose methotrexate. The prognostic value of the other two predictors may be directly related to their relationship with β-hCG concentrations. According to Lipscomb and colleagues (1999), an initial serum value <5000 IU/L was associated with a success rate of 92 percent, whereas an initial concentration >15,000 IU/L had a success rate of 68 percent. In another study, Menon and associates (2007) reported that compared with an initial serum β-hCG level of 2000 to 4999 IU/L, an initial serum β-hCG of 5000 to 9999 IU/L is nearly four times more likely to be associated with methotrexate therapy failure.

The effect of size on success rates with medical therapy has fewer supporting data, although many early trials used “large size” as an exclusion criterion. In one study, the success rate with single-dose methotrexate was 93 percent in cases with ectopic masses <3.5 cm, whereas success rates were between 87 and 90 percent when the mass was >3.5 cm (Lipscomb, 1998).

Identification of cardiac activity sonographically is a relative contraindication to medical therapy, although this is based on limited evidence. Most studies report an increased risk of failure if there is cardiac activity, however, a success rate of 87 percent has been reported (Lipscomb, 1998).

Of predictors of treatment failure, extrauterine yolk sac as a predictor of methotrexate failure has conflicting evidence (Lipscomb, 2009). Rapidly rising β-hCG levels both before (>50 percent) and during methotrexate therapy may also portend an increased failure risk (American Society for Reproductive Medicine, 2013; Dudley, 2004).

Methotrexate

This folic acid antagonist competitively inhibits the binding of dihydrofolic acid to the enzyme dihydrofolate reductase. This leads to reduced amounts of purines and thymidylate and thereby an arrest of DNA, RNA, and protein synthesis (Chap. 27). It inhibits fast-growing tissue and is used for cancer chemotherapy and for early IUP termination. The drug can be given orally, intravenously, or intramuscularly (IM) or can be directly injected into the ectopic pregnancy sac. Currently, IM methotrexate administration is used most commonly for tubal ectopic pregnancies.

Prior to therapy, serum creatinine and β-hCG levels, a complete blood count, liver function tests, and blood type and Rh status are obtained (American Society for Reproductive Medicine, 2013). Moreover, all except blood typing are repeated prior to additional doses (Lipscomb, 2007). With administration, women are counseled to avoid the following until treatment is completed: folic acid-containing supplements, which can competitively reduce methotrexate binding to dihydrofolate reductase; nonsteroidal antiinflammatory drugs, which reduce renal blood flow and delay drug excretion; alcohol, which can predispose to concurrent hepatic enzyme elevation; sunlight, which can provoke methotrexate-related dermatitis; and coitus, which can rupture the ectopic pregnancy (American College of Obstetricians and Gynecologists, 2014). Importantly, methotrexate is a teratogen and is a Food and Drug Administration pregnancy category X. As such, it can lead to a profound embryopathy that includes intrauterine growth retardation and cardiac, craniofacial, and skeletal abnormalities (Nurmohamed, 2011).

The most common side effects of methotrexate include stomatitis, conjunctivitis, and transient liver dysfunction, although myelosuppression, mucositis, pulmonary damage, and anaphylactoid reactions have been reported with only one dose of 50 to 100 mg (Isaacs, 1996; Straka, 2004). Side effects are seen in as many as a third of women treated, however, they are usually self-limited. In some cases, leucovorin (folinic acid) is given following treatment to blunt or reverse methotrexate side effects. Such therapy is termed leucovorin rescue (Chap. 27).

The single-dose and multidose methotrexate protocols shown in Table 7-3 are associated with overall resolution rates for ectopic pregnancy that approximate 90 percent. To date, Alleyassin and coworkers (2006) have completed the only randomized trial comparing single and multidose administrations. Although the study was underpowered to detect a small difference in success rates, they did observe that 89 percent in the single-dose group and 93 percent in the multidose group were successfully treated. When analyzed from the standpoint of treatment failure, single-dose therapy had a 50-percent higher failure rate compared with multidose therapy (6/54 versus 4/54). Lipscomb and colleagues (2005) reviewed their institutional experience with methotrexate therapy in 643 consecutively treated patients. They found no significant differences in treatment duration, serum β-hCG levels, or success rates between the multi- and single-dose protocols—95 and 90 percent, respectively. Barnhart and coworkers (2003a) performed a metaanalysis of 26 studies that included 1327 women treated with methotrexate for ectopic pregnancy. Single-dose therapy was more commonly used because of simplicity. It was less expensive, was easily accepted because of less intensive posttherapy monitoring, and did not require leucovorin rescue (Alexander, 1996). The major limitation was that multidose treatment had a fivefold greater chance of success than single-dose therapy. Failures included women with tubal rupture, massive intraabdominal hemorrhage, and need for urgent surgery and blood transfusions. Ultimately, most women received between one and four doses of methotrexate. Interestingly, the initial serum β-hCG value was not a valid indicator of how many doses of methotrexate a patient would need for a successful outcome (Nowak-Markwitz, 2009). In the absence of adequately powered randomized trials comparing single- with multidose therapy, we use single-dose IM methotrexate.

Single-Dose Methotrexate

This regimen is the most widely used medical treatment of ectopic pregnancy. Of various doses, the most popular is the 50 mg/m² body surface area (BSA) protocol (Stovall, 1993). BSA can be derived using various Internet-based BSA calculators such as: http://www.globalrph.com/bsa2.htm.

Close monitoring is imperative. A serum β-hCG level is determined prior to methotrexate administration and is repeated on days 4 and 7 following injection. Levels usually continue to rise until day 4. Comparison is then made between day 4 and 7 serum values. If there is a decline by 15 percent or more, then weekly serum β-hCG levels are drawn until they measure <2 IU/L. A decline of less than 15 percent is seen in approximately 20 percent of treated women. In such cases, a second 50 mg/m² dose is given, and the protocol is restarted. One review of more than 1700 cases showed that if a second dose is needed, then a day 1 serum β-hCG level <2234 IU/L could be considered a predictor of ultimate treatment success (Cohen, 2014). Approximate time to resolution for all women averages 36 days, but in some, treatment requires as long as 109 days (Lipscomb, 1998). Others have tried, without success, to develop more convenient serum β-hCG monitoring protocols (Kirk, 2007; Thurman, 2010). In the end, the original day-4-to-7 guidelines have been validated.

During the first few days following methotrexate administration, up to half of women experience abdominal pain that can be controlled with mild analgesics. This separation pain presumably results from tubal distention caused by tubal abortion or hematoma formation or both (Stovall, 1993). In some cases, inpatient observation with serial hematocrit determinations and gentle abdominal examinations help assess the need for surgical intervention.

Multidose Methotrexate

The most common regimen is seen in Table 7-3 and consists of up to four doses of parenteral methotrexate, followed by adjunctive doses of leucovorin 24 hours later. Serial serum β-hCG concentrations are obtained. If there is not a 15-percent decline from the previous value—for example, days 1 to 3—an additional methotrexate/leucovorin dose is given, and the serum β-hCG level is repeated 2 days later. A maximum of four doses are given, and weekly serum β-hCG level surveillance continues until values are undetectable.

A hybrid “two dose” protocol strives to balance the efficacy and convenience of the two most commonly used protocols (Barnhart, 2007). The regimen administers 50 mg/m² of methotrexate on days 0 and 4 without leucovorin rescue. Although the protocol is still considered experimental, no safety concerns were noted in the 101 patients treated, and the success rate approached 87 percent. A recent comparison of the single dose and “two dose” methotrexate protocols found equivalent success rates (87 and 90 percent, respectively) with a trend toward increased needs for repeated doses in the single-dose cohort (Gungorduk, 2011).

Other Medical Options

The bioavailability of oral and parenteral methotrexate is similar, but few trials have evaluated oral methotrexate for ectopic pregnancy treatment. Korhonen and coworkers (1996) randomly assigned women with candidate tubal pregnancies to be managed expectantly or to receive low-dose oral methotrexate, 2.5 mg daily for 5 days. They found no differences in primary treatment success.

Mifepristone is a progesterone antagonist and is effective for evacuation of first-trimester IUPs (Chap. 6). Logically, the addition of mifepristone, 600 mg orally, to single-dose methotrexate might improve unruptured ectopic pregnancy resolution. However, in a randomized trial of 212 cases, success rates did not differ if mifepristone was added (Rozenberg, 2003).

Direct injection of methotrexate with sonographic or laparoscopic guidance into an ectopic pregnancy aims to minimize systemic side effects of methotrexate. Pharmacokinetic studies with 1 mg/kg of methotrexate injected either into the sac or by traditional IM injection showed similar success rates. However, fewer drug-related side effects were seen with local injection (Fernandez, 1995).

Direct injection of 50-percent glucose into the ectopic mass using laparoscopic guidance was 94-percent successful in one small prospective trial for women with serum β-hCG levels <2500 IU/L (Yeko, 1995). Gjelland and coworkers (1995) reported that the treatment success rate was significantly better in a similar population in which sonographically rather than laparoscopically guided injection was used.

Surveillance

Posttherapy monitoring assesses treatment success and screens for signs of persistent ectopic pregnancy. Most medical management protocols have well-defined surveillance schedules. In the absence of symptoms, bimanual examinations are deferred to avoid the theoretical risk of manual tubal rupture. Importantly, sonographic monitoring of ectopic mass dimensions can be misleading after serum β-hCG levels have declined to <15 IU/L. Brown and colleagues (1991) described persistent masses to be resolving hematomas rather than persistent trophoblastic tissue. For this reason, posttherapy sonography is reserved for suspected complications such as tubal rupture. Most recommend contraception for 3 to 6 months after successful medical therapy with methotrexate, as this drug may persist in human tissues for up to 8 months after a single dose (Warkany, 1978).

Surgical Management

Laparotomy versus Laparoscopy

At least three prospective studies have compared laparotomy with laparoscopic surgery for ectopic pregnancies (Lundorff, 1991; Murphy, 1992; Vermesh, 1989). In sum, investigators found no significant differences in overall tubal patency determined at second-look laparoscopy. This was despite higher rates of ipsilateral adhesions in the laparotomy group. Each method was followed by a similar number of subsequent intrauterine pregnancies. Fewer repeat ectopic pregnancies were noted in women treated laparoscopically, although this difference was not significant. Laparoscopy offered shorter operative times, less blood loss, fewer analgesic requirements, and shorter hospital stays. Laparoscopic surgery was significantly less successful in resolving the tubal pregnancy, but this was balanced by the just-mentioned benefits of minimally invasive surgery.

With improvements in laparoscopic equipment and with accrued experience, cases previously managed by laparotomy, such as ruptured tubal or intact interstitial pregnancies, can now be considered for laparoscopy in those with commensurate skills (Sagiv, 2001). Among experienced surgeons, shorter operating times and expedited hemorrhage control are both advantages of laparoscopic intervention for ruptured ectopic pregnancies (Cohen, 2013).

Laparotomy offers a potential advantage to laparoscopy if salpingostomy is planned. A metaanalysis using data from two trials concluded that compared with laparotomic salpingostomy, laparoscopic salpingostomy leads to one case of persistent trophoblastic disease for every 12 women undergoing the laparoscopic approach (Mol, 2008).

Laparoscopy

Two randomized trials have been completed to date to guide the choice between conservative—laparoscopic salpingostomy, and definitive—laparoscopic salpingectomy. The European Surgery in Ectopic Pregnancy (ESEP) study randomly assigned 446 women with a healthy contralateral fallopian tube to salpingectomy or salpingostomy (Mol, 2014). In the DEMETER trial patients were also randomly selected for either of these surgeries. Similar to the ESEP study, results from the DEMETER trial showed no differences in 2-year subsequent IUP rates (64 versus 70 percent, respectively) whether salpingectomy or salpingostomy was used for ectopic pregnancy removal (Fernandez, 2013). Thus, if the contralateral fallopian tube appears normal, then salpingectomy is a reasonable treatment option that avoids the 5 to 8 percent complication rate caused by persistent or recurrent ectopic pregnancy in the same tube (Rulin, 1995).

For laparoscopic salpingectomy, many techniques have been described, and a surgical description is found in Section 44-3. Lim and associates (2007) compared electrosurgical coagulation of the tube and mesosalpinx during laparoscopic salpingectomy with laparoscopic suture-loop (Endoloop) ligation. Endoloop use was associated with significantly shorter operating times (48 versus 61 minutes) and lower postoperative pain scores.

For laparoscopic salpingostomy, a woman who is hemodynamically stable and strongly desires to preserve fertility is an appropriate candidate. This applies especially if the other fallopian tube is absent or damaged. Serum β-hCG levels may be a factor in patient selection. One retrospective study found that ectopic resolution rates were lower following salpingostomy in women in whom the initial serum β-hCG level was >8000 IU/L (Milad, 1998). Supportive evidence for this comes from Natale and associates (2003), who reported that serum β-hCG levels >6000 IU/L have a high risk of implantation into the tubal muscularis.

As illustrated in Section 44-4, during salpingostomy, the ectopic tissue can be flushed or grasped from the tubal incision. All free and tubal placental tissue should be meticulously removed, as retained trophoblast in the tube can lead to later invasion and bleeding. Other cases of persistent serum β-hCG levels are explained by trophoblastic tissue that is dropped during ectopic extraction and then subsequently implants intraabdominally (Bucella, 2009).

Medical versus Surgical Therapy

Several randomized trials have compared methotrexate treatment with laparoscopic surgery. One multicenter trial compared a multidose methotrexate protocol with laparoscopic salpingostomy and found no differences for tubal preservation and primary treatment success (Hajenius, 1997). However, in this same study group, health-related quality of life factors such as pain, posttherapy depression, and decreased perception of health were significantly impaired after systemic methotrexate compared with laparoscopic salpingostomy (Nieuwkerk, 1998).

Evidence is conflicting when single-dose methotrexate is compared with surgical intervention. In two separate studies, single-dose methotrexate was overall less successful in resolving pregnancy than laparoscopic salpingostomy, although tubal patency and subsequent uterine pregnancy rates were similar between both groups (Fernandez, 1998; Sowter, 2001). Krag Moeller and associates (2009) reported during a median surveillance period of 8.6 years that ectopic-resolution success rates were not significantly different between those managed surgically and those treated with methotrexate. Moreover, cumulative spontaneous intrauterine pregnancy rates were not different between the methotrexate group (73 percent) and the surgical group (62 percent).

Based on these studies, we conclude that women who are hemodynamically stable and in whom there is a small tubal diameter, no fetal cardiac activity, and serum β-hCG concentrations <5000 IU/L have similar outcomes with medical or surgical management. Despite lower success rates with medical therapy for women with larger tubal size, higher serum β-hCG levels, and fetal cardiac activity, medical management can be offered to the motivated woman who understands the risks of emergency surgery in the event of treatment failure.

Expectant Management

In select women, close observation, in anticipation that there will be spontaneous resorption of an ectopic pregnancy, is reasonable. Intuitively, it is difficult to accurately predict which woman will have an uncomplicated course with such management. Although an initial serum β-hCG concentration best predicts outcome, the range varies widely. For example, initial values <200 IU/L predict successful spontaneous resolution in 88 to 96 percent of attempts, whereas values >2000 IU/L had success rates of only 20 to 25 percent (Elson, 2004; Trio, 1995). Even with declining values, when the initial β-hCG level exceeded 2000 IU/L, the success rate was only 7 percent (Shalev, 1995). Interestingly, in this study, there was no difference in ipsilateral tubal patency or 1-year fertility rates with either success or failure of expectant management.

Close monitoring is warranted because the risk of tubal rupture persists despite low and declining serum β-hCG levels. An argument could be made that the minimal side effects of methotrexate make it preferable to a potentially prolonged surveillance and associated patient anxiety.

Persistent Ectopic Pregnancy

Incomplete eradication of trophoblastic tissue and its continued growth causes tubal rupture in 3 to 20 percent of women following conservative surgical or medical treatment of ectopic pregnancy (Graczykowski, 1999). Thus, abdominal pain following conservative management prompts immediate suspicion for persistent trophoblast proliferation.

Following salpingostomy, persistent ectopic pregnancy is more likely with very early pregnancies. Specifically, surgical management is more difficult because pregnancies smaller than 2 cm are harder to visualize and completely remove. To obviate this, Graczykowski and associates (1997) administered a prophylactic dose of 1 mg/m² methotrexate postoperatively, which reduced the incidence of persistent ectopic pregnancy and length of surveillance. Again, this is balanced against methotrexate side effects.

The optimal monitoring schedule to identify persistent ectopic pregnancy after surgical therapy has not been determined. Protocols describe serum β-hCG level monitoring from every 3 days to every 2 weeks. Spandorfer and associates (1997) estimated the risk of persistent ectopic pregnancy based on serum β-hCG levels done on the first postoperative day after salpingostomy. They observed that if serum β-hCG levels fell by >50 percent compared with presurgical values, then there were no treatment failures within the first 9 days, and thus repeat serum β-hCG determinations 1 week after surgery were appropriate. Conversely, if serum levels fell by <50 percent, then there was a 3.5-fold increased risk of failure within the first week, thus necessitating earlier postoperative evaluation. Importantly, despite low and falling serum β-hCG concentrations, tubal rupture can still occur (Tulandi, 1991). Currently, standard therapy for persistent ectopic pregnancy is single-dose methotrexate given IM at a dose of 50 mg/m² BSA.

Ectopic implantation of the fertilized egg in the ovary is rare and is diagnosed if four clinical criteria are met. These were outlined by Spiegelberg (1878) and include: (1) the ipsilateral tube is intact and distinct from the ovary; (2) the ectopic pregnancy occupies the ovary; (3) the ectopic pregnancy is connected by the uteroovarian ligament to the uterus; and (4) ovarian tissue can be demonstrated histologically in the placental tissue. A more recent increased incidence in ovarian pregnancy likely is artifactual due to improved imaging. Risk factors are similar to those for tubal pregnancies. In one review, 24 percent of a total of 110 ovarian ectopic pregnancies were in IUD users (Ko, 2012). Nearly a third of women with an ovarian pregnancy present with hemodynamic instability because of rupture. Diagnosis is based on the classic sonographic description of a cyst with a wide echogenic outer ring on or within the ovary (Comstock, 2005). With smaller ectopic pregnancies, ovarian wedging can be considered (Ko, 2012). For larger lesions, oophorectomy is often required.

Interstitial pregnancies implant in the proximal tubal segment that lies within the muscular uterine wall. Swelling lateral to the insertion of the round ligament is the characteristic anatomic finding (Fig. 7-10). Incorrectly, these are sometimes called cornual pregnancies, but this term describes conceptions that develop in the horns of uteri with müllerian anomalies (Lau, 1999; Moawad, 2010). In the past, interstitial pregnancies usually ruptured following 8 to 16 weeks of amenorrhea. This later gestational age at rupture is attributed to the greater distensibility of the myometrium covering the fallopian tube’s interstitial segment. Risk factors are similar to others discussed, although prior ipsilateral salpingectomy is a specific risk factor for interstitial pregnancy (Lau, 1999). Because of the proximity of these pregnancies to the uterine and ovarian arteries, hemorrhage with rupture can be severe and is associated with mortality rates as high as 2.5 percent (Tulandi, 2004).

Distinct from interstitial pregnancy, the term angular pregnancy describes intrauterine implantation in one of the lateral angles of the uterus and medial to the uterotubal junction and round ligament. This distinction is important because angular pregnancies can sometimes be carried to term but with increased risk of abnormal placentation and uterine rupture (Arleo, 2014; Jansen, 1981). Improved imaging modalities, such as 3-dimensional sonography, may help differentiate eccentrically located gestational sacs from an interstitial pregnancy (Singh, 2015; Tanaka, 2014).

For interstitial pregnancies, surgical management involves cornual resection by either laparotomy or laparoscopy (Section 43-9). As discussed for suspected tubal pregnancy, interstitial pregnancy can now often be diagnosed early enough to consider conservative medical therapy (Bernstein, 2001). Given its low incidence, no consensus regarding prediction of success using methotrexate has been established. Jermy and colleagues (2004) reported a 94-percent success with systemic methotrexate in 17 women using a dose of 50 mg/m² BSA. Their series included four women in whom fetal cardiac activity was verified. Because these women have higher initial serum β-hCG levels at diagnosis, longer surveillance is usually needed. Deruelle and coworkers (2005) advocate adjuvant postmethotrexate uterine artery embolization to help avert hemorrhage and hasten ectopic pregnancy resolution. Of other therapies, uterine artery methotrexate infusion and embolization combined with systemic methotrexate has shown promising results (Hiersch, 2014; Krissi, 2014). Hysteroscopic resection or transcervical suction curettage of interstitial pregnancies has been described (Sanz, 2002; Zhang, 2004).

Following either medical or conservative surgical management, the risk of uterine rupture with subsequent pregnancies is unclear. Thus, careful observation of these women during pregnancy, along with strong consideration of elective cesarean delivery, is warranted.

The incidence of cervical pregnancy is reported to be between 1 in 8600 and 1 in 12,400 pregnancies (Ushakov, 1997). The incidence appears to be rising because of ART, especially IVF and embryo transfer (Ginsburg, 1994; Pattinson, 1994). A risk factor unique to cervical pregnancy is a history of dilatation and curettage in a prior pregnancy and is seen in nearly 70 percent of cases (Hung, 1996; Pisarska, 1999). Two diagnostic criteria are necessary for cervical pregnancy confirmation: (1) cervical glands are found opposite the placental attachment site, and (2) a portion of or the entire placenta is located below either the entrance of the uterine vessels or the peritoneal reflection on the anterior and posterior uterine surface (Fig. 7-11).

For most hemodynamically stable women with a first-trimester cervical pregnancy, nonsurgical management with systemic methotrexate can be offered and administered as in Table 7-3. Jeng and colleagues (2007) also described 38 cases successfully treated with methotrexate injection into the gestational sac. Resolution and uterine preservation is achieved with methotrexate regimens for gestations <12 weeks in 91 percent of cases (Kung, 1997). In selecting appropriate candidates, Hung and colleagues (1996) noted higher risks of systemic methotrexate treatment failure in those with a gestational age >9 weeks, β-hCG levels >10,000 IU/L, crown-rump length >10 mm, and fetal cardiac activity. For this reason, many induce fetal death with intracardiac or intrathoracic injection of potassium chloride (Jeng, 2007; Verma, 2009). Uterine artery embolization, either before or after methotrexate administration, may be an additional adjunct to limit bleeding complications (Cipullo, 2008; Hirakawa, 2009).

Although conservative management is feasible for many women with cervical pregnancies, surgical intervention may also be selected. Procedures include suction curettage or hysterectomy. Moreover, in those with advanced gestations or with bleeding uncontrolled by conservative methods, hysterectomy is typically required. Importantly, patients should understand the increased risk of urinary tract injury with hysterectomy due to the close proximity of the ureters to the ballooned cervix. Prior to either procedure, uterine artery embolization may be considered to limit intra- and postoperative bleeding (Nakao, 2008; Trambert, 2005). In addition, before curettage, local methotrexate injection into the amnionic sac, ligation of the descending branches of the uterine arteries, or cerclage placement at the internal os to compress feeding vessels have all been described (Davis, 2008; De La Vega, 2007; Mesogitis, 2005; Trojano, 2009). Following curettage, in the event of hemorrhage, a 26F Foley catheter with a 30-mL balloon can be placed intracervically and inflated to effect hemostasis and to monitor uterine drainage (Ushakov, 1997). In addition, uterine artery embolization may be considered.

A uterine pregnancy in conjunction with an extrauterine pregnancy is termed a heterotopic pregnancy. In the past, the incidence was estimated to be 1 in 30,000 pregnancies. In pregnancies resulting from ART, the heterotopic pregnancies rate approximates 0.09 percent (Perkins, 2015). For a tubal pregnancy coexistent with a uterine pregnancy, potassium chloride can be injected into the tubal pregnancy sac. Methotrexate is contraindicated due to the detrimental effects on the normal pregnancy.

Implantation within the scar of a prior cesarean delivery through a microscopic tract in the myometrium is uncommon (Fig. 7-12). Similar to other ectopic pregnancies, it carries significant risks of massive hemorrhage. Reviews cite the incidence of cesarean scar pregnancy (CSP) to approximate 1 in 2000 pregnancies (Sadeghi, 2010). These microscopic tracts can also stem from other prior uterine surgery—curettage, myomectomy, operative hysteroscopy—and perhaps from manual removal of the placenta (Ash, 2007).

Differentiating between a pregnancy with low implantation and a cesarean scar pregnancy can be difficult, and several investigators have described sonographic findings (Jurkovic, 2003; Moschos, 2008a). According to Godin (1997), four sonographic criteria should be satisfied for the diagnosis: (1) an empty uterine cavity, (2) an empty cervical canal, (3) a gestational sac in the anterior part of the uterine isthmus, and (4) absence of healthy myometrium between the bladder and gestational sac.

Treatment standards are lacking, but options include systemic or locally injected methotrexate, either alone or combined with suction curettage or hysteroscopic removal (Shen, 2012; Timor-Tritsch, 2012; Yang, 2010). Isthmic resection with a double layer closure can be performed open, laparoscopically, or robotically (Hudecek, 2014). With any of the options, uterine artery embolization may be used adjunctively to minimize hemorrhage (Zhuang, 2009). In most cases, the uterus can be preserved, although hysterectomy is also an acceptable and sometimes necessary option (Sadeghi, 2010).

Abdominal pregnancy is an implantation in the peritoneal cavity exclusive of tubal, ovarian, or intraligamentous implantations. These are rare and have an estimated incidence of 1 in 10,000 to 25,000 live births (Atrash, 1987; Worley, 2008). Ectopic placental implantations in less expected sites have been described in case reports and include the omentum, spleen, liver, and retroperitoneum, among others (Chin, 2010; Chopra, 2009; Gang, 2010; Martínez-Varea, 2011). Also rare, ectopic pregnancies have been reported in women with prior hysterectomy (Fylstra, 2010). Presumably, a vaginal cuff fistula, a prolapsed fallopian tube, or a cervical stump after supracervical hysterectomy allows sperm to access an ovulated ovum.

Prevention is difficult because few ectopic pregnancy risk factors are modifiable (Butts, 2003). Tubal pathology carries one of the highest risks, and pelvic inflammatory disease (PID) plays a major role in tubal adhesions and obstruction. Chlamydial infections constitute nearly half of PID cases, thus efforts have been directed toward screening high-risk populations for asymptomatic infections. These include sexually active women <25 years or women with risk factors (Table 1-1). Such screening programs in Sweden have demonstrated steady declines in both chlamydial infections and ectopic pregnancy rates, especially in women aged 20 to 24 years (Cates, 1999; Egger, 1998).