Williams Obstetrics, 24th Edition

CHAPTER 19. Ectopic Pregnancy

TUBAL PREGNANCY

CLINICAL MANIFESTATIONS

MULTIMODALITY DIAGNOSIS

MEDICAL MANAGEMENT

SURGICAL MANAGEMENT

INTERSTITIAL PREGNANCY

ABDOMINAL PREGNANCY

OVARIAN PREGNANCY

CERVICAL PREGNANCY

CESAREAN SCAR PREGNANCY

Following fertilization and fallopian tube transit, the blastocyst normally implants in the endometrial lining of the uterine cavity. Implantation elsewhere is considered ectopic and comprises 1 to 2 percent of all first-trimester pregnancies in the United States. This small proportion disparately accounts for 6 percent of all pregnancy-related deaths (Berg, 2010; Stulberg, 2013). In addition, the chance for a subsequent successful pregnancy is reduced after an ectopic pregnancy. Fortunately, urine and serum beta-human chorionic gonadotropin (β-hCG) assays and transvaginal sonography have made earlier diagnosis possible. And as a result, both maternal survival rates and conservation of reproductive capacity are improved.

TUBAL PREGNANCY

image Classification

Nearly 95 percent of ectopic pregnancies are implanted in the various segments of the fallopian tube and give rise to fimbrial, ampullary, isthmic, or interstitial tubal pregnancies (Fig. 19-1). As shown, the ampulla is the most frequent site, followed by the isthmus. The remaining 5 percent of nontubal ectopic pregnancies implant in the ovary, peritoneal cavity, cervix, or prior cesarean scar. Occasionally, a multifetal pregnancy is composed of one conceptus with normal uterine implantation coexisting with one implanted ectopically. The natural incidence of these heterotopic pregnancies approximates 1 per 30,000 pregnancies. However, because of assisted reproductive technologies (ART), their incidence has increased to 1 in 7000 overall, and following ovulation induction, it may be as high as 0.5 to 1 percent (Mukul, 2007). Rarely, twin tubal pregnancy with both embryos in the same tube or with one in each tube has been reported (Eze, 2012; Svirsky, 2010).

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FIGURE 19-1 Sites of implantation of 1800 ectopic pregnancies from a 10-year population-based study. (Data from Callen, 2000; Bouyer, 2003.)

Regardless of location, D-negative women with an ectopic pregnancy who are not sensitized to D-antigen should be given IgG anti-D immunoglobulin (American College of Obstetricians and Gynecologists, 2013). In first-trimester pregnancies, a 50-μg or a 300-μg dose is appropriate, whereas a standard 300-μg dose is used for later gestations.

image Risks

Abnormal fallopian tube anatomy underlies many cases of tubal ectopic pregnancy. Surgeries for a prior tubal pregnancy, for fertility restoration, or for sterilization confer the highest risk of tubal implantation. After one previous ectopic pregnancy, the chance of another approximates 10 percent (Ankum, 1996; Skjeldestad, 1998). Prior sexually transmitted disease or other tubal infection, which can distort normal tubal anatomy, is another common risk factor. Specifically, one episode of salpingitis can be followed by a subsequent ectopic pregnancy in up to 9 percent of women (Westrom, 1992). Similarly, peritubal adhesions subsequent to salpingitis, appendicitis, or endometriosis may increase the risk for tubal pregnancy. Salpingitis isthmica nodosa, which is a condition in which epithelium-lined diverticula extend into a hypertrophied muscularis layer, also poses an increased risk (Schippert, 2012). Congenital fallopian tube anomalies, especially those secondary to in utero diethylstilbestrol exposure, can also lead to malformed tubes and higher ectopic rates (Hoover, 2011).

Infertility, per se, as well as the use of ART to overcome it, is linked to substantively increased risks for ectopic pregnancy (Clayton, 2006). And “atypical” implantations—cornual, abdominal, cervical, ovarian, and heterotopic pregnancy—are more common following ART procedures. Smoking is also a known association, although the underlying mechanism is unclear (Waylen, 2009). Last, with any form of contraception, the absolute number of ectopic pregnancies is decreased because pregnancy occurs less often. However, with some contraceptive method failures, the relative number of ectopic pregnancies is increased. Examples include tubal sterilization, copper and progestin-releasing intrauterine devices (IUDs), and progestin-only contraceptives (Furlong, 2002).

image Evolution and Potential Outcomes

With tubal pregnancy, because the fallopian tube lacks a submucosal layer, the fertilized ovum promptly burrows through the epithelium. The zygote comes to lie near or within the muscularis, which is invaded in most cases by rapidly proliferating trophoblast. The embryo or fetus in an ectopic pregnancy is often absent or stunted.

Outcomes of ectopic pregnancy include tubal rupture, tubal abortion, or pregnancy failure with resolution. With rupture, the invading expanding products of conception and associated hemorrhage may tear rents in the fallopian tube at any of several sites. As a rule, if the tube ruptures in the first few weeks, the pregnancy is most likely located in the isthmic portion, whereas the ampulla is slightly more distensible (Fig. 19-2). However, if the fertilized ovum implants within the interstitial portion, rupture usually occurs later. Tubal ectopic pregnancies usually burst spontaneously but may occasionally rupture following coitus or bimanual examination.

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FIGURE 19-2 Ruptured ampullary early tubal pregnancy. (Photograph contributed by Dr. Togas Tulandi.)

Alternatively, the pregnancy may abort out the distal fallopian tube, and the frequency of this depends in part on the initial implantation site. Abortion is common in fimbrial and ampullary pregnancies, whereas rupture is the usual outcome with those in the tubal isthmus. With tubal abortion, hemorrhage disrupts the connection between the placenta and membranes and the tubal wall. If placental separation is complete, the entire conceptus may be extruded through the fimbriated end into the peritoneal cavity. At this point, hemorrhage may cease and symptoms eventually disappear. Some bleeding usually persists as long as products remain in the tube. Blood slowly trickles from the tubal fimbria into the peritoneal cavity and typically pools in the rectouterine cul-de-sac. If the fimbriated extremity is occluded, the fallopian tube may gradually become distended by blood, forming a hematosalpinx.

Last, an unknown number of ectopic pregnancies spontaneously fail and are reabsorbed. This may be documented now more regularly with the advent of sensitive β-hCG assays.

There are differences between “acute” ectopic pregnancy just described and “chronic” ectopic pregnancy. The more common acute ectopic pregnancies are those with a high serum β-hCG level and rapid growth, leading to an immediate diagnosis. These carry a higher risk of tubal rupture (Barnhart, 2003c). With chronic ectopic pregnancy, abnormal trophoblast die early, and thus negative or lower, static serum β-hCG levels are found (Brennan, 2000). Chronic ectopic pregnancies typically rupture late, if at all, but commonly form a complex pelvic mass, which often is the reason prompting diagnostic surgery (Cole, 1982; Grynberg, 2009; Uğur, 1996).

image Clinical Manifestations

Earlier patient presentation and more precise diagnostic technology typically allow identification before rupture. In these cases, symptoms and signs of ectopic pregnancy are often subtle or even absent. The woman does not suspect tubal pregnancy and assumes that she has a normal early pregnancy or is having a miscarriage.

With later diagnosis, a “classic” presentation is characterized by the triad of delayed menstruation, pain, and vaginal bleeding or spotting. With tubal rupture, there is usually severe lower abdominal and pelvic pain that is frequently described as sharp, stabbing, or tearing. There is tenderness during abdominal palpation. Bimanual pelvic examination, especially cervical motion, causes exquisite pain. The posterior vaginal fornix may bulge from blood in the rectouterine cul-de-sac, or a tender, boggy mass may be felt to one side of the uterus. Although minimal early, later the uterus may be pushed to one side by an ectopic mass. The uterus may also be slightly enlarged due to hormonal stimulation. Symptoms of diaphragmatic irritation, characterized by pain in the neck or shoulder, especially on inspiration, develop in perhaps half of women with sizable hemoperitoneum.

Some degree of vaginal spotting or bleeding is reported by 60 to 80 percent of women with tubal pregnancy. Although profuse vaginal bleeding is suggestive of an incomplete abortion, such bleeding occasionally is seen with tubal gestations. Moreover, tubal pregnancy can lead to significant intraabdominal hemorrhage. Responses to moderate bleeding include no change in vital signs, a slight rise in blood pressure, or a vasovagal response with bradycardia and hypotension. Birkhahn and colleagues (2003) noted that in 25 women with ruptured ectopic pregnancy, most at presentation had a heart rate < 100 beats per minute and a systolic blood pressure > 100 mm Hg. Blood pressure will fall and pulse will rise only if bleeding continues and hypovolemia becomes significant. Vasomotor disturbances develop, ranging from vertigo to syncope.

Even after substantive hemorrhage, hemoglobin or hematocrit readings may at first show only a slight reduction. Hence, after an acute hemorrhage, a decline in hemoglobin or hematocrit level over several hours is a more valuable index of blood loss than is the initial level. In approximately half of women with a ruptured ectopic pregnancy, varying degrees of leukocytosis up to 30,000/μL may be documented.

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 takes the form of the endometrial cavity (Fig. 19-3). Importantly, decidual sloughing may also occur with uterine abortion. Thus, tissue should be 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 considered.

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FIGURE 19-3 This decidual cast was passed by a patient with a tubal ectopic pregnancy. The cast mirrors the shape of the endometrial cavity, and each arrow marks the portion of decidua that lined the cornua.

image Multimodality Diagnosis

The differential diagnosis for abdominal pain coexistent with pregnancy is extensive. Pain may derive from uterine conditions such as miscarriage, infection, degenerating or enlarging leiomyomas, molar pregnancy, or round-ligament pain. Adnexal disease may include ectopic pregnancy; hemorrhagic, ruptured, or torsed ovarian masses; salpingitis; or tuboovarian abscess. Last, appendicitis, cystitis, renal stone, or gastroenteritis may be nongynecological sources of lower abdominal pain in early pregnancy.

A number of algorithms have been proposed to identify ectopic pregnancy. Most include these key components: physical findings, transvaginal sonography (TVS), serum β-hCG level measurement—both the initial and the subsequent pattern of rise or decline, and diagnostic surgery, which includes uterine curettage, laparoscopy, and occasionally, laparotomy (Fig. 19-4). Algorithm use applies only to hemodynamically stable women—those with presumed rupture should undergo prompt surgical therapy. For a suspected unruptured ectopic pregnancy, all diagnostic strategies involve trade-offs. Strategies that maximize detection of ectopic pregnancy may result in termination of a normal pregnancy. Conversely, those that reduce the potential for normal pregnancy interruption will delay ectopic pregnancy diagnosis. Patient desires for the index pregnancy are also discussed and may influence these trade-offs.

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FIGURE 19-4 One suggested algorithm for evaluation of a woman with a suspected ectopic pregnancy. aExpectant management, D&C, or medical regimens are suitable options. bSerial serum β-hCG levels may be appropriate if a normal uterine pregnancy or if completed abortion is suspected clinically. β-hCG = beta human chorionic gonadotropin; D&C = dilatation and curettage; IUP = intrauterine pregnancy; TVS = transvaginal sonography. (Modified from Gala, 2012.)

Beta Human Chorionic Gonadotropin

Rapid and accurate determination of pregnancy is essential to identify an ectopic pregnancy. Current serum and urine pregnancy tests that use enzyme-linked immunosorbent assays (ELISAs) for β-hCG are sensitive to levels of 10 to 20 mIU/mL and are positive in > 99 percent of ectopic pregnancies (Kalinski, 2002). Rare cases of chronic ectopic pregnancy, described earlier, with negative serum β-hCG assay results have been reported.

With bleeding or pain and a positive pregnancy test result, an initial TVS is typically performed to identify gestation location. If a yolk sac, embryo, or fetus is identified within the uterus or the adnexa, then a diagnosis can be made. In many cases however, TVS is nondiagnostic, and tubal pregnancy is still a possibility. In these cases in which neither intrauterine nor extrauterine pregnancy is identified, the term pregnancy of unknown location (PUL) is used until additional clinical information allows determination of pregnancy location.

Levels above the Discriminatory Zone. A number of investigators have described discriminatory β-hCG levels above which failure to visualize an intrauterine pregnancy (IUP) indicates that the pregnancy either is not alive or is ectopic. Barnhart and colleagues (1994) reported that an empty uterus with a serum β-hCG concentration ≥ 1500 mIU/mL was 100-percent accurate in excluding a live uterine pregnancy. Some institutions set their discriminatory threshold higher at ≥ 2000 mIU/mL. Moreover, Connolly and associates (2013) reported evidence to suggest an even higher threshold. They noted that with live uterine pregnancies, a gestational sac was seen 99 percent of the time with a discriminatory level of 3510 mIU/mL.

If the initial β-hCG level exceeds the set discriminatory level and no evidence for a uterine pregnancy is seen with TVS, then the diagnosis is narrowed in most cases to a failed uterine pregnancy, completed abortion, or an ectopic pregnancy. Early multifetal gestation also remains a possibility. If there is a suspicion in a stable patient that a PUL could be a normal pregnancy, it is prudent to continue expectant management with serial β-hCG level assessment to avoid harming an early normal pregnancy. If patient history or extruded uterine tissue suggests a completed abortion, then serial β-hCG levels will drop rapidly. Otherwise, curettage will distinguish an ectopic from a nonliving uterine pregnancy. Some do not recommend diagnostic curettage because it results in unnecessary surgical therapy (Barnhart, 2002). This is countered by concern for methotrexate toxicity if this drug is given erroneously to women with a presumed ectopic pregnancy.

Levels below the Discriminatory Zone. If the initial β-hCG level is below the set discriminatory value, pregnancy location is often not technically discernible with TVS. With these PULs, serial β-hCG level assays are done to identify patterns that indicate either a growing or failing uterine pregnancy. Levels that rise or fall outside these expected parameters increase the concern for ectopic pregnancy. Thus, appropriately selected women with a possible ectopic pregnancy, but whose initial β-hCG level is below the discriminatory threshold, are seen 2 days later for further evaluation. First, with early normal progressing uterine pregnancies, Kadar and Romero (1987) reported that mean doubling time for serum β-hCG levels was approximately 48 hours. The lowest normal value for this increase was 66 percent. Barnhart and coworkers (2004) reported a 53-percent 48-hour minimum rise with a 24-hour minimum rise of 24 percent. Seeber and associates (2006) used an even more conservative 35-percent 48-hour rise. Importantly, Silva and colleagues (2006) caution that a third of women with an ectopic pregnancy will have a 53-percent rise at 48 hours. They further reported that no single pattern characterizes ectopic pregnancy and that approximately half of ectopic pregnancies will show decreasing β-hCG levels, whereas the other half will have increasing levels.

With a failing intrauterine pregnancy, patterned rates of β-hCG level decline can also be anticipated. Rates of decline ranging between 21 and 35 percent are commonly used. As seen in Table 19-1, the percentage drop is greater if the initial β-hCG level is higher.

TABLE 19-1. Expected Minimum Percentage Decline of Initial Serum β-hCG Levels to Subsequently Drawn Values for Nonliving Pregnancies

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In pregnancies without these expected rises or falls in β-hCG levels, distinction between a nonliving intrauterine and an ectopic pregnancy may be aided by repeat β-hCG level evaluation (Zee, 2013). Also, uterine curettage is an option. Barnhart and associates (2003b) reported that endometrial biopsy was less sensitive than curettage. Before curettage, a second TVS examination may be indicated and may display new informative findings.

Serum Progesterone

A single serum progesterone measurement may clarify the diagnosis in a few cases (Stovall, 1989, 1992b). A value exceeding 25 ng/mL excludes ectopic pregnancy with 92.5-percent sensitivity (Lipscomb, 1999a; Pisarska, 1998). Conversely, values below 5 ng/mL are found in only 0.3 percent of normal pregnancies (Mol, 1998). Thus, values < 5 ng/mL suggest either a nonliving uterine pregnancy or an ectopic pregnancy. Because in most ectopic pregnancies, progesterone levels range between 10 and 25 ng/mL, the clinical utility is limited (American College of Obstetricians and Gynecologists, 2012). One caveat is that pregnancy achieved with ART may be associated with higher than usual progesterone levels (Perkins, 2000).

A number of preliminary studies have been done to evaluate novel markers to detect ectopic pregnancy (Rausch, 2012; Senapati, 2013). However, none of these are in current clinical use.

Transvaginal Sonography

Endometrial Findings. In a woman in whom ectopic pregnancy is suspected, TVS is performed to look for findings indicative of intrauterine or ectopic pregnancy. During endometrial cavity evaluation, an intrauterine 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 (Fig. 9-3p. 170). With transabdominal sonography, these structures are visualized slightly later.

In contrast, with ectopic pregnancy, a trilaminar endometrial pattern can be diagnostic (Fig. 19-5). Its specificity is 94 percent, but with a sensitivity of only 38 percent (Hammoud, 2005). In addition, Moschos and Twickler (2008b) determined that in women with PUL at presentation, no normal pregnancies had a stripe thickness < 8 mm.

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FIGURE 19-5 Transvaginal sonography of a pseudogestational sac within the endometrial cavity. Its cavity-conforming shape and central location are characteristic of these anechoic fluid collections. Distal to this fluid, the endometrial stripe has a trilaminar pattern, which is a common finding with ectopic pregnancy. (Image contributed by Dr. Elysia Moschos.)

Anechoic fluid collections, which might normally suggest an early intrauterine gestational sac, may also be seen with ectopic pregnancy. These include pseudogestational sac and decidual cyst. First, a pseudosac is a fluid collection between the endometrial layers and conforms to the cavity shape (see Fig. 19-5). If a pseudosac is noted, the risk of ectopic pregnancy is increased (Hill, 1990; Nyberg, 1987). Second, a decidual cyst is identified as an anechoic area lying within the endometrium but remote from the canal and often at the endometrial-myometrial border. Ackerman and colleagues (1993b) suggested that this finding represents early decidual breakdown and precedes decidual cast formation.

These two findings contrast with the intradecidual sign seen with intrauterine pregnancy. This is an early gestational sac and is eccentrically located within one of the endometrial stripe layers (Dashefsky, 1988). The American College of Obstetricians and Gynecologists (2011) advises caution in diagnosing a uterine pregnancy in the absence of a definite yolk sac or embryo.

Adnexal Findings. The sonographic diagnosis of ectopic pregnancy rests on visualization of an adnexal mass separate from the ovary (Fig. 19-6). If fallopian tubes and ovaries are visualized and an extrauterine yolk sac, embryo, or fetus is identified, then an ectopic pregnancy is clearly confirmed. In other cases, a hyperechoic halo or tubal ring surrounding an anechoic sac can be seen. 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). Importantly, not all adnexal masses represent an ectopic pregnancy, and integration of sonographic findings with other clinical information is necessary.

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FIGURE 19-6 Various transvaginal sonographic findings with ectopic tubal pregnancies. For sonographic diagnosis, an ectopic mass should be seen in the adnexa separate from the ovary and may be seen as: (A) a yolk sac (shown here) and/or fetal pole with or without cardiac activity within an extrauterine sac, (B) an empty extrauterine sac with a hyperechoic ring, or (C) an inhomogeneous adnexal mass. In this last image, color Doppler shows a classic “ring of fire,” which reflects increased vascularity typical of ectopic pregnancies. LT OV = left ovary; SAG LT AD = sagittal left adnexal; UT = uterus.

Placental blood flow within the periphery of the complex adnexal mass—the ring of fire—can be seen with transvaginal color Doppler imaging. Although this can aid in the diagnosis, this finding can also be seen with a corpus luteum of pregnancy, and differentiation can be challenging.

Hemoperitoneum. In women with suspected ectopic pregnancy, evaluation for hemoperitoneum can add valuable clinical information. More commonly, this is completed using sonography, but assessment can also be made by culdocentesis. Sonographically, hemoperitoneum is anechoic or hypoechoic fluid. Blood initially collects in the dependent retrouterine cul-de-sac, and then additionally surrounds the uterus as it fills the pelvis (Fig. 19-7). As little as 50 mL can be seen in the cul-de-sac using TVS, and transabdominal imaging helps to assess the hemoperitoneum extent. For example, with significant intraabdominal hemorrhage, blood will track up the pericolic gutters to fill Morison pouch near the liver. Free fluid in this pouch typically is not seen until accumulated blood reaches 400 to 700 mL (Branney, 1995; Rodgerson, 2001; Rose, 2004). Diagnostically, peritoneal fluid in conjunction with an adnexal mass is highly predictive of ectopic pregnancy (Nyberg, 1991). Importantly, however, a small amount of peritoneal fluid is physiologically normal.

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FIGURE 19-7 Techniques to identify hemoperitoneum. A. Transvaginal sonography of an anechoic fluid collection (arrow) in the retrouterine cul-de-sac. B. Culdocentesis: with a 16- to 18-gauge spinal needle attached to a syringe, the cul-de-sac is entered through the posterior vaginal fornix as upward traction is applied to the cervix with a tenaculum.

Culdocentesis is a simple technique used commonly in the past to identify hemoperitoneum. The cervix is pulled outward and upward toward the symphysis with a tenaculum, and a long 18-gauge needle is inserted through the posterior vaginal fornix into the retrouterine cul-de-sac. If present, fluid can be aspirated. However, a failure to do so is interpreted only as unsatisfactory entry into the cul-de-sac and does not exclude ectopic pregnancy. Fluid containing fragments of old clots or bloody fluid that does not clot is compatible with the diagnosis of hemoperitoneum. In contrast, if the blood sample clots, it may have been obtained from an adjacent blood vessel or from a briskly bleeding ectopic pregnancy. A number of studies have challenged its usefulness, and culdocentesis has been largely replaced by TVS (Glezerman, 1992; Vermesh, 1990).

Laparoscopy

Direct visualization of the fallopian tubes and pelvis by laparoscopy offers a reliable diagnosis in most cases of suspected ectopic pregnancy. There is also a ready transition to definitive operative therapy, which is discussed subsequently.

image Treatment Options

Options for ectopic tubal pregnancy treatment include medical and surgical approaches, and their comparison is discussed on page 387. Medical therapy traditionally involves the antimetabolite methotrexate. Surgical choices include mainly salpingostomy or salpingectomy.

image Medical Management

Regimen Options

Methotrexate is a folic acid antagonist. It tightly binds to dihydrofolate reductase, blocking the reduction of dihydrofolate to tetrahydrofolate, which is the active form of folic acid. As a result, de novo purine and pyrimidine synthesis is halted, which leads to arrested DNA, RNA, and protein synthesis. Thus, methotrexate is highly effective against rapidly proliferating tissue such as trophoblast, and overall ectopic tubal pregnancy resolution rates approximate 90 percent with its use. However, bone marrow, gastrointestinal mucosa, and respiratory epithelium can also be harmed. It is directly toxic to hepatocytes and is renally excreted. Importantly, methotrexate is a potent teratogen, and methotrexate embryopathy is notable for craniofacial and skeletal abnormalities and fetal-growth restriction (Chap. 12p. 248) (Nurmohamed, 2011). In addition, methotrexate is excreted into breast milk and may accumulate in neonatal tissues and interfere with neonatal cellular metabolism (American Academy of Pediatrics, 2001; Briggs, 2011). Based on all these findings, a list of contraindications and pretherapy laboratory testing is found in Table 19-2. Methotrexate is bound primarily to albumin, and its displacement by other medications such as phenytoin, tetracyclines, salicylates, and sulfonamides can increase methotrexate serum drug levels. Moreover, renal clearance of methotrexate may be impaired by nonsteroidal antiinflammatory drugs, probenecid, aspirin, or penicillins (Stika, 2012). Last, vitamins containing folic acid may lower methotrexate efficacy.

TABLE 19-2. Medical Treatment Protocols for Ectopic Pregnancy

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For ease and efficacy, intramuscular methotrexate administration is used most frequently for ectopic pregnancy resolution, and single-dose and multidose methotrexate protocols are available (see Table 19-2). As noted, methotrexate can lead to bone marrow depression. This toxicity can be blunted by early administration of leucovorin, which is folinic acid and has activity equivalent to folic acid. Thus, leucovorin, which is given within the multidose protocol, allows for some purine and pyrimidine synthesis to buffer side effects.

In comparing these two protocols, trade-offs are recognized. For example, single-dose therapy offers simplicity, less expense, and less intensive posttherapy monitoring and does not require leucovorin rescue. However, some but not all studies report a higher success rate for the multidose regimen (Alleyassin, 2006; Barnhart, 2003a; Lipscomb, 2005). At our institution, we use single-dose methotrexate.

A third hybrid “two dose” protocol has been proposed in an effort to balance the efficacy and convenience of the two most commonly used protocols (Barnhart, 2007). The regimen involves administering 50 mg/m2 of methotrexate on days 0 and 4 without leucovorin rescue. Data are limited on its comparative efficacy with the two standard regimens, but one study showed single-dose to be as effective as the two-dose regimen (Gungorduk, 2011).

Patient Selection

The best candidate for medical therapy is the woman who is asymptomatic, motivated, and compliant. With medical therapy, some classic predictors of success include a low initial serum β-hCG level, small ectopic pregnancy size, and absent fetal cardiac activity. Of these, initial serum β-hCG level is the single best prognostic indicator of successful treatment with single-dose methotrexate. Specifically, reported failure rates are 1.5 percent if the initial serum β-hCG concentration is < 1000 mIU/mL; 5.6 percent with 1000 to 2000 mIU/mL; 3.8 percent with 2000 to 5000 mIU/mL; and 14.3 percent when levels are between 5000 and 10,000 mIU/mL (Menon, 2007). Interestingly, the initial serum β-hCG value is not a valid indicator of the number of doses needed for successful resolution (Nowak-Markwitz, 2009).

Many early trials also used “large size” as an exclusion criterion, although these data are less precise. Lipscomb and colleagues (1998) reported a 93-percent success rate with single-dose methotrexate when the ectopic mass was < 3.5 cm. This compared with success rates between 87 and 90 percent when the mass was > 3.5 cm. Last, most studies report increased failure rates if there is cardiac activity. Lipscomb and colleagues (1998) reported an 87-percent success rate in such cases.

Treatment Side Effects

These regimens are associated with minimal laboratory changes and symptoms, although occasional toxicity may be severe. Kooi and Kock (1992) reviewed 16 studies and reported that adverse effects were resolved by 3 to 4 days after methotrexate was discontinued. The most common were liver involvement—12 percent, stomatitis—6 percent, and gastroenteritis—1 percent. One woman had bone marrow depression. Regarding long-term effects, Oriol and coworkers (2008), using antimüllerian hormone assays, concluded that ovarian reserve was not compromised by single-dose methotrexate therapy.

Importantly, 65 to 75 percent of women initially given methotrexate will have increasing pain beginning several days after therapy. This separation pain generally is mild and relieved by analgesics. In a series of 258 methotrexate-treated women by Lipscomb and colleagues (1999b), 20 percent had pain severe enough to require evaluation in the clinic or emergency room. Ultimately, 10 of these 53 underwent surgical exploration. Said another way, 20 percent of women given single-dose methotrexate will have significant pain, and 20 percent of these will require laparoscopy.

Overall, the failure rate is similar for either medical or surgical management. In three randomized trials, 5 to 14 percent of women treated initially with methotrexate ultimately required surgery, whereas 4 to 20 percent of those undergoing laparoscopic resection eventually received methotrexate for persistent trophoblast (Fernandez, 1998; Hajenius, 1997, 2007; Saraj, 1998). Rupture of persistent ectopic pregnancy is the worst form of primary therapy failure and occurs in 5 to 10 percent of women treated medically. Lipscomb and associates (1998) described a 14-day mean time to rupture, but one woman had tubal rupture 32 days after single-dose methotrexate.

Monitoring Therapy Efficacy

Serum β-hCG levels are used to monitor response to both medical and surgical therapy. After linear salpingostomy, serum β-hCG levels decline rapidly over days and then more gradually, with a mean resolution time of approximately 20 days. In contrast, after single-dose methotrexate, mean serum β-hCG levels increase for the first 4 days, and then gradually decline, with a mean resolution time of 27 days. Lipscomb and colleagues (1998) used single-dose methotrexate to successfully treat 287 women and reported that the average time to resolution—defined as a serum β-hCG level < 15 mIU/mL, was 34 days. Importantly, the longest time was 109 days.

As shown in Table 19-2, monitoring single-dose therapy calls for serum β-hCG determinations at days 4 and 7 following initial injection on day 1. If the level fails to drop more than 15 percent between days 4 and 7, then a second dose of methotrexate is required. This is necessary in 15 to 20 percent of women treated with single-dose therapy. With multidose methotrexate, levels are measured at 48-hour intervals until they fall more than 15 percent. Once appropriately dropping levels are achieved in either regimen, serum β-hCG determinations are then measured weekly until undetectable. Outpatient surveillance is preferred, but if there is any question of safety or compliance, the woman is hospitalized. Failure is judged when the β-hCG level plateaus or rises or tubal rupture occurs. Importantly, tubal rupture can occur in the face of declining β-hCG levels.

image Surgical Management

Laparoscopy is the preferred surgical treatment for ectopic pregnancy unless a woman is hemodynamically unstable. There have been only a few prospective studies that compare laparotomy with laparoscopic surgery. Hajenius and associates (2007) performed a Cochrane Database review and found that subsequent uterine pregnancy rates and tubal patency rates in those treated with salpingostomy were comparable with either abdominal entry route. Subsequent ectopic pregnancies were fewer in women treated laparoscopically, although this was not statistically significant. As experience has accrued, cases previously managed by laparotomy—for example, ruptured tubal pregnancies or interstitial pregnancies—can safely be managed laparoscopically by those with suitable expertise. Before surgery, future fertility desires of the patient should be discussed. In those desiring permanent sterilization, the unaffected tube can be ligated concurrently with salpingectomy for the affected fallopian tube.

Tubal surgery is considered conservative when there is tubal salvage, such as with salpingostomy. Radical surgery is defined by salpingectomy. Some have shown conservative surgery may increase the rate of subsequent uterine pregnancy but is associated with higher rates of persistently functioning trophoblast (Bangsgaard, 2003; de Bennetot, 2012). This may not be the case, however. In a randomized controlled trial, Fernandez and associates (2013) evaluated 2-year rates of attaining an intrauterine pregnancy following either salpingostomy or salpingectomy. Although pregnancy rates with salpingectomy were 64 percent compared with 71 percent following salpingostomy, these differences were not statistically significant.

Salpingostomy

This procedure is typically used to remove a small unruptured pregnancy that is usually < 2 cm in length and located in the distal third of the fallopian tube (Fig. 19-8). Natale and associates (2003) reported that serum β-hCG levels > 6000 mIU/mL are associated with a higher risk of implantation into the muscularis and thus with more tubal damage.

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FIGURE 19-8 Linear salpingostomy for ectopic pregnancy. A. A linear incision for removal of a small tubal pregnancy is created on the antimesenteric border of the tube. B. Products of conception may be flushed from the tube using an irrigation probe. Alternatively, products may be removed with grasping forceps. Following evacuation of the tube, bleeding sites are treated with electrosurgical coagulation. The incision is not sutured. (From Thompson, 2012, with permission.)

With surgery, a 10- to 15-mm linear incision is made on the antimesenteric border over the pregnancy. The products usually will extrude from the incision. These can be carefully removed or flushed out using high-pressure irrigation that more thoroughly removes the trophoblastic tissue (Al-Sunaidi, 2007). Small bleeding sites are controlled with needlepoint electrocoagulation, and the incision is left unsutured to heal by secondary intention.

Seldom performed today, salpingotomy is essentially the same procedure as salpingostomy except that the incision is closed with delayed-absorbable suture. According to Tulandi and Guralnick (1991), there is no difference in prognosis with or without suturing.

Salpingectomy

Tubal resection may be used for both ruptured and unruptured ectopic pregnancies. To minimize the rare recurrence of pregnancy in the tubal stump, complete excision of the fallopian tube is advised. With one laparoscopic technique, the affected fallopian tube is lifted and held with atraumatic grasping forceps (Thompson, 2012). One of several suitable bipolar grasping devices is placed across the fallopian tube at the uterotubal junction. Once desiccated, the tube is cut. The bipolar device is then advanced across the most proximal portion of mesosalpinx. Similarly, current is applied, and the desiccated tissue cut. This process moves serially from the proximal mesosalpinx to its distal extent under the tubal ampulla. Alternatively, an endoscopic suture loop can be used to encircle and ligate the knuckle of fallopian tube that contains the ectopic pregnancy and its underlying vascular supply within the mesosalpinx. Two consecutive suture loops are placed, and the tube distal to these ligatures is then cut free with scissors.

Most tubal ectopic pregnancies are small and pliant. Accordingly, they can be held firmly by grasping forceps and drawn up into one of the accessory site cannulas. Larger tubal ectopic pregnancies may be placed in an endoscopic sac to prevent fragmentation as they are removed through the laparoscopic port site. Importantly, to remove all trophoblastic tissue, the pelvis and abdomen should be irrigated and suctioned free of blood and tissue debris. Slow and systematic movement of the patient from Trendelenburg to reverse Trendelenburg positioning during irrigation can also assist in dislodging stray tissue and fluid. These should be suctioned and removed from the peritoneal cavity.

Persistent Trophoblast

Incomplete removal of trophoblast may result in persistent trophoblastic tissue. This complicates 5 to 20 percent of salpingostomies and can be identified by stable or rising β-hCG levels. Usually, β-hCG levels fall quickly and are at approximately 10 percent of preoperative values by day 12 (Hajenius, 1995; Vermesh, 1988). Also, if the postoperative day 1 serum β-hCG value is less than 50 percent of the preoperative value, then persistent trophoblast rarely is a problem (Spandorfer, 1997). According to Seifer (1997), factors that increase the risk of persisting trophoblast include: pregnancies less than 2 cm, early pregnancy less than 42 menstrual days, serum β-hCG level > 3000 mIU/mL, or implantation medial to the salpingostomy site. With stable or increasing β-hCG levels, additional surgical or medical therapy is necessary. Currently, standard therapy for this is single-dose methotrexate, 50 mg/m2 × body surface area (BSA). To prevent persistent trophoblastic tissue, some advocate postoperative administration of “prophylactic” methotrexate with a dose of 1 mg/m2 BSA (Akira, 2008; Graczykowski, 1997).

image 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). In their randomized controlled trial, Fernandez and coworkers (2013) compared multidose medical therapy against salpingostomy and found that medical and conservative surgery provided similar 2-year rates of attaining an intrauterine pregnancy.

There is conflicting evidence 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). Women treated with methotrexate had significantly better physical functioning immediately following therapy, but there were no differences in psychological functioning. Krag Moeller and associates (2009) reported the results from their randomized trial that had a median surveillance period of 8.6 years during which future pregnancy rates were evaluated. 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 mIU/mL 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.

image Expectant Management

In select cases, it is reasonable to observe very early tubal pregnancies that are associated with stable or falling serum β-hCG levels. As many as a third of such women will present with declining β-hCG levels (Shalev, 1995). Stovall and Ling (1992a) restrict expectant management to women with tubal ectopic pregnancies only, decreasing serial β-hCG levels, diameter of the ectopic mass ≤ 3.5 cm, and no evidence of intraabdominal bleeding or rupture by transvaginal sonography. Mavrelos and coworkers (2013) noted that almost one third of 333 tubal ectopic pregnancies measuring < 3 cm and with β-hCG levels < 1500 mIU/mL resolved without intervention. Noted by the American College of Obstetricians and Gynecologists (2012), 88 percent of ectopic pregnancies will resolve if the β-hCG is < 200 mIU/mL.

With expectant management, subsequent rates of tubal patency and intrauterine pregnancy are comparable with surgery and medical management. The potentially grave consequences of tubal rupture, coupled with the established safety of medical and surgical therapy, require that expectant therapy be undertaken only in appropriately selected and counseled women.

INTERSTITIAL PREGNANCY

image Diagnosis

These pregnancies implant within the proximal tubal segment that lies within the muscular uterine wall (Fig. 19-9). Incorrectly, they may be called cornual pregnancies, but this term describes a conception that develops in the rudimentary horn of a uterus with a müllerian anomaly. Risk factors are similar to others discussed for tubal ectopic pregnancy, although previous ipsilateral salpingectomy is a specific risk factor for interstitial pregnancy (Lau, 1999). Undiagnosed interstitial pregnancies usually rupture following 8 to 16 weeks of amenorrhea, which is later than for more distal tubal ectopic pregnancies. This is due to greater distensibility of the myometrium covering the interstitial fallopian tube segment. Because of the proximity of these pregnancies to the uterine and ovarian arteries, there is a risk of severe hemorrhage, which is associated with mortality rates as high as 2.5 percent (Tulandi, 2004).

image

FIGURE 19-9 Interstitial ectopic pregnancy. A. This parasagittal view using transvaginal sonography shows an empty uterine cavity and a mass that is cephalad and lateral to the uterine fundus (calipers). B.Intraoperative photograph during laparotomy and before cornual resection of the same ectopic pregnancy. In this frontal view, the bulging right-sided interstitial ectopic pregnancy is lateral to the round ligament insertion and medial to the isthmic portion of the fallopian tube. (Photograph contributed by Drs. David Rogers and Elaine Duryea.)

With TVS and serum β-hCG assays, interstitial pregnancy can now be diagnosed early in many cases, but diagnosis can be challenging. These pregnancies sonographically can appear similar to an eccentrically implanted intrauterine pregnancy, especially in a uterus with a müllerian anomaly. Criteria that may aid differentiation include: an empty uterus, a gestational sac seen separate from the endometrium and > 1 cm away from the most lateral edge of the uterine cavity, and a thin, < 5-mm myometrial mantle surrounding the sac (Timor-Tritsch, 1992). Moreover, an echogenic line, known as the “interstitial line sign,” extending from the gestational sac to the endometrial cavity most likely represents the interstitial portion of the fallopian tube and is highly sensitive and specific (Ackerman, 1993a). In unclear cases, three-dimensional sonography, magnetic resonance (MR) imaging, or diagnostic laparoscopy may also provide clarification (Izquierdo, 2003; Parker, 2012). Laparoscopically, an enlarged protuberance lying outside the round ligament coexistent with normal distal fallopian tubes and ovaries is found.

image Management

Surgical management with either cornual resection or cornuostomy may be performed via laparotomy or laparoscopy, depending on patient hemodynamic stability and surgeon expertise (Word, 2012; Zuo, 2012). With either approach, intraoperative intramyometrial vasopressin injection may limit surgical blood loss, and β-hCG levels should be monitored postoperatively to exclude remnant trophoblast. Cornual resection removes the gestational sac and surrounding cornual myometrium by means of a wedge excision (Fig. 19-10). Alternatively, cornuostomy involves incision of the cornua and suction or instrument extraction of the pregnancy.

image

FIGURE 19-10 During cornual resection, the pregnancy, surrounding myometrium, and ipsilateral fallopian tube are excised en bloc. The incision is angled inward as it is deepened. This creates a characteristic wedge shape into the myometrium, which is then closed in layers with delayed-absorbable suture. The serosa is closed with subcuticular style suturing. (From Word, 2012, with permission.)

With early diagnosis, conservative medical management may be considered. However, because of the low incidence, consensus regarding methotrexate route or regimen is lacking. In their small series, Jermy and associates (2004) reported a 94-percent success with systemic methotrexate using a dose of 50 mg/m2 BSA. Others have described direct methotrexate injection into the gestational sac (Timor-Tritsch, 1996). Importantly, because these women typically have higher initial serum β-hCG levels at diagnosis, longer surveillance is usually needed.

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

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 its consequences (Jansen, 1981).

ABDOMINAL PREGNANCY

image Diagnosis

Strictly defined, abdominal pregnancy is an implantation in the peritoneal cavity exclusive of tubal, ovarian, or intraligamentous implantations. These are rare ectopic pregnancies with an estimated incidence of 1 in 10,000 to 25,000 live births (Atrash, 1987; Worley, 2008). Although a zygote can traverse the tube and implant primarily in the peritoneal cavity, most abdominal pregnancies are thought to follow early tubal rupture or abortion with reimplantation. In cases of advanced extrauterine pregnancy, it is not unusual that the placenta is still at least partially attached to the uterus or adnexa (Fig. 19-11).

image

FIGURE 19-11 Sagittal view of an abdominal pregnancy at term. The placenta is implanted on the posterior surface of the uterus and broad ligament. The enlarged, flattened uterus is located just beneath the anterior abdominal wall and to the level of the umbilicus. The cervix and vagina are pulled up and are dislodged anteriorly and superiorly by the large fetal head in the cul-de-sac.

Diagnosis may be difficult. First, symptoms may be absent or vague. Laboratory tests are typically uninformative, although maternal serum alpha-fetoprotein levels may be elevated. Clinically, abnormal fetal positions may be palpated, or the cervix is displaced (Zeck, 2007). Sonographically, findings with an abdominal pregnancy may not be recognized, and the diagnosis is often missed (Costa, 1991). Oligohydramnios is common but nonspecific. Other clues include a fetus seen separate from the uterus or eccentrically positioned within the pelvis; lack of myometrium between the fetus and the maternal anterior abdominal wall or bladder; and extrauterine placental tissue (Sherer, 2007). If additional anatomical information is needed, MR imaging can be used to confirm the diagnosis and provide maximal information concerning placental implantation (Bertrand, 2009; Mittal, 2012).

image Management

An abdominal pregnancy can be life-threatening, and management depends on the gestational age at diagnosis. Some describe waiting until fetal viability with close surveillance (Gomez, 2008; Varma, 2003). Of note, Stevens (1993) reported fetal malformations and deformations in 20 percent. The most common malformations were limb deficiency and central nervous system anomalies. The most common deformations were facial and/or cranial asymmetry and various joint abnormalities. Conservative management also carries a maternal risk for sudden and dangerous hemorrhage. We are of the opinion that termination generally is indicated when the diagnosis is made. Certainly, before 24 weeks, conservative treatment rarely is justified.

Once placental implantation has been assessed, several options are available. Preoperative angiographic embolization has been used successfully in some women with advanced abdominal pregnancy. Alternatively, catheters placed in the uterine arteries may be inflated to decrease intraoperative blood loss. In either case, vascularization of ectopic placental implantation may be difficult to occlude. Other preoperative considerations include insertion of ureteral catheters, bowel preparation, assurance of sufficient blood products, and availability of a multidisciplinary surgical team or elective transfer to a tertiary care facility. In many ways, surgical management is similar to that for placenta percreta, which is detailed in Chapter 41 (p. 807).

The principal surgical objectives involve delivery of the fetus and careful assessment of placental implantation without provoking hemorrhage. Unnecessary exploration is avoided because the anatomy is commonly distorted and surrounding areas will be extremely vascular. Importantly, placental removal may precipitate torrential hemorrhage because the normal hemostatic mechanism of myometrial contraction to constrict hypertrophied blood vessels is lacking. If it is obvious that the placenta can be safely removed or if there is already hemorrhage from its implantation site, then removal begins immediately. When possible, blood vessels supplying the placenta should be ligated first.

Some advocate leaving the placenta in place as the lesser of two evils. It decreases the chance of immediate life-threatening hemorrhage, but at the expense of long-term sequelae. If left in the abdominal cavity, the placenta commonly becomes infected, with subsequent formation of abscesses, adhesions, intestinal or ureteral obstruction, and wound dehiscence (Bergstrom, 1998; Martin, 1988). In many of these cases, surgical removal becomes inevitable. If the placenta is left, its involution may be monitored using sonography and serum β-hCG levels (France, 1980; Martin, 1990). Color Doppler sonography can be used to assess changes in blood flow. In some cases, and usually depending on its size, placental function rapidly declines, and the placenta is resorbed. However, placental resorption may take years (Roberts, 2005; Valenzano, 2003).

If the placenta is left in place, postoperative methotrexate use is controversial. It has been recommended to hasten involution but has been reported to cause accelerated placental destruction with accumulation of necrotic tissue and infection with abscess formation (Rahman, 1982). It is difficult to envision a supporting role for the use of an antimetabolite for a senescent organ (Worley, 2008).

INTRALIGAMENTOUS PREGNANCY

In zygotes implanted toward the mesosalpinx, rupture may occur at the portion of the tube not immediately covered by peritoneum. The gestational contents may then be extruded into a space formed between the broad ligament leaves and become an intraligamentous or broad ligament pregnancy. These are rare, and information accrues from case reports (Seckin, 2011). Clinical findings and management mirror those for abdominal pregnancy. Although laparotomy is required in most instances, a few case reports describe laparoscopic excision of early small pregnancies (Apantaku, 2006; Cormio, 2006).

OVARIAN PREGNANCY

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): (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 amid the placental tissue (Fig. 19-12). Risk factors are similar to those for tubal pregnancies, but ART or IUD failure seems to be disproportionately associated (Ko, 2012). Presenting complaints and findings mirror tubal ectopic pregnancy. Although the ovary can accommodate the expanding pregnancy more easily than the fallopian tube, rupture at an early stage is the usual consequence.

image

FIGURE 19-12 Ovarian pregnancy. A. Transvaginal sonogram shows a gestational sac containing fetal parts of a 16-week gestation. The placenta is marked by a red asterisk. B. Due to concern for extensive parasitic blood supply to the pregnancy, exploratory laparotomy was performed. Here, the right ovary is lifted by the surgeon, and the fallopian tube is the cordlike structure stretched across the top of the mass. Due to mass size and vascularity and scant normal ovarian stroma, this patient was treated by right salpingo-oophorectomy. (Photograph contributed by Dr. Kyler Elwell.)

TVS use has resulted in a more frequent diagnosis of unruptured ovarian pregnancies. Sonographically, an internal anechoic area is surrounded by a wide echogenic ring, which in turn is surrounded by ovarian cortex (Comstock, 2005). In their review of 49 cases, Choi and associates (2011) noted that the diagnosis may not be made until surgery as many cases are presumed tubal ectopic pregnancy. Moreover, at surgery, an early ovarian pregnancy may be considered to be a hemorrhagic corpus luteum cyst or a bleeding corpus luteum.

Evidence-based management accrues mainly from case reports (Hassan, 2012; Scutiero, 2012). Classically, management for ovarian pregnancies has been surgical. Small lesions have been managed by ovarian wedge resection or cystectomy, whereas larger lesions require oophorectomy. Finally, systemic or locally injected methotrexate has been used successfully to treat small unruptured ovarian pregnancies (Pagidas, 2013). With conservative surgery or medical management, β-hCG levels should be monitored to exclude remnant trophoblast.

CERVICAL PREGNANCY

image Diagnosis

This ectopic pregnancy is defined by cervical glands noted histologically opposite the placental attachment site and by part or all of the placenta found below the entrance of the uterine vessels or below the peritoneal reflection on the anterior uterus. In a typical case, the endocervix is eroded by trophoblast, and the pregnancy develops in the fibrous cervical wall. The more cephalad that the trophoblast is implanted along the cervical canal, the greater is its capacity to grow and hemorrhage. The incidence of cervical pregnancy lies between 1 in 8600 and 1 in 12,400 pregnancies, but the incidence is increasing as a result of ART (Ginsburg, 1994). Another risk according to Jeng and colleagues (2007) is previous dilation and curettage.

Painless vaginal bleeding is reported by 90 percent of women with a cervical pregnancy—a third of these have massive hemorrhage (Ushakov, 1997). As pregnancy progresses, a distended, thin-walled cervix with a partially dilated external os may be evident. Above the cervical mass, a slightly enlarged uterine fundus can be felt. Identification of cervical pregnancy is based on speculum examination, palpation, and TVS. Sonographic findings typical of cervical pregnancy are shown and described in Figure 19-13. MR imaging and 3-D sonography have also been used to confirm the diagnosis (Jung, 2001; Sherer, 2008).

image

FIGURE 19-13 Cervical pregnancy. Transvaginal sonographic findings may include: (1) an hourglass uterine shape and ballooned cervical canal; (2) gestational tissue at the level of the cervix (black arrow); (3) absent intrauterine gestational tissue (white arrows); and (4) a portion of the endocervical canal seen interposed between the gestation and the endometrial canal. (Image contributed by Dr. Elysia Moschos.)

image Management

Cervical pregnancy may be treated medically or surgically. In many centers, including ours, methotrexate has become the first-line therapy in stable women, and administration follows protocols listed in Table 19-2 (Verma, 2011; Zakaria, 2011). The drug has also been injected directly into the gestational sac, alone or with systemic doses (Jeng, 2007; Kirk, 2006). Others describe methotrexate infusion combined with uterine artery embolization (Xiaolin, 2010). With methotrexate regimens, resolution and uterine preservation are achieved 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 mIU/mL, crown-rump length > 10 mm, and fetal cardiac activity. For this reason, many induce fetal death with intracardiac or intrathoracic injection of potassium chloride. With a single-dose intramuscular methotrexate protocol, a dose between 50 and 75 mg/m2 BSA is typical. For women in whom fetal cardiac activity is detectable, a sonographically guided fetal intracardiac injection of 2 mL (2 mEq/mL) potassium chloride solution can be given (Verma, 2009). If β-hCG levels do not decline more than 15 percent after 1 week, a second dose of methotrexate can be given. Song and associates (2009) described management of 50 cases and observed that sonographic resolution lagged far behind serum β-hCG regression.

As an adjunct to medical or surgical therapy, uterine artery embolization has been described either as a response to bleeding or as a preprocedural preventive tool (Hirakawa, 2009; Nakao, 2008; Zakaria, 2011). The specifics of this interventional radiological technique are detailed in Chapter 41 (p. 820). Also in the event of hemorrhage, a 26F Foley catheter with a 30-mL balloon can be placed intracervically and inflated to effect hemostasis by vessel tamponade and to monitor uterine drainage. The balloon remains inflated for 24 to 48 hours and is gradually decompressed over a few days (Ushakov, 1997).

Although conservative management is feasible for many women with cervical pregnancies, suction curettage or hysterectomy may be selected. Moreover, hysterectomy may be required with bleeding uncontrolled by conservative methods. Unfortunately, due to the close proximity of the ureters to the ballooned cervix, urinary tract injury rates are of concern with hysterectomy.

Suction curettage may be especially favored in rare cases of a heterotopic pregnancy composed of a cervical and a desired uterine pregnancy (Moragianni, 2012). If cervical curettage is planned, intraoperative bleeding may be lessened by preoperative uterine artery embolization, by ligation of the descending branches of the uterine arteries, by vasopressin injection, or by a cerclage placed at the internal cervical os to compress feeding vessels (Davis, 2008; De La Vega, 2007; Trojano, 2009; Wang, 2011). Of these, cervical branches of the uterine artery can effectively be ligated with placement of hemostatic cervical sutures on the lateral aspects of the cervix at 3 and 9 o’clock. Cerclage placement is described in Chapter 18 (p. 361). Following curettage, a Foley balloon is placed to tamponade bleeding and is managed as described earlier.

CESAREAN SCAR PREGNANCY

This term describes implantation within the myometrium of a prior cesarean delivery scar. Its incidence approximates 1 in 2000 normal pregnancies and has increased alongside the cesarean delivery rate (Ash, 2007; Rotas, 2006). The pathogenesis of cesarean scar pregnancy (CSP) has been likened to that for placenta accreta and carries similar risk for serious hemorrhage (Timor-Tritsch, 2012a). It is unknown if the incidence increases with multiple cesarean deliveries or if it is affected by either one- or two-layer uterine incision closure.

Women with CSP usually present early, and pain and bleeding are common. However, up to 40 percent of women are asymptomatic, and the diagnosis is made during routine sonographic examination (Rotas, 2006). Rarely, early rupture can lead to an abdominal pregnancy (Teng, 2007).

Sonographically, differentiating between a cervicoisthmic intrauterine pregnancy and CSP can be difficult, and several investigators have described sonographic findings (Jurkovic, 2003; Moschos, 2008a). According to Godin (1997), there are four sonographic criteria that should be satisfied for the diagnosis, which are shown and described in Figure 19-14. Although TVS is the typical first-line imaging tool, MR imaging is useful when sonography is equivocal or inconclusive before intervention (Osborn, 2012).

image

FIGURE 19-14 Cesarean scar pregnancy. A. Transvaginal sonogram of a uterus with a cesarean scar pregnancy (CSP) in a sagittal plane. An empty uterine cavity is identified by a bright hyperechoic endometrial stripe (long, white arrow). An empty cervical canal is similarly identified (short, white arrow). Last, an intrauterine mass is seen in the anterior part of the uterine isthmus (red arrows). healthy myometrium between the bladder and gestational sac is absent. (Image contributed by Dr. Elysia Moschos.) B. Hysterectomy specimen containing a cesarean scar pregnancy. C. This same hysterectomy specimen is transversely sectioned at the level of the uterine isthmus and through the gestational sac. The uterine body lies to the left, and the cervix is on the right. A metal probe is placed through the endocervical canal to show the eccentric development of this gestation. Only a thin layer of myometrium overlies this pregnancy, which pushes anteriorly through the uterine wall. (Photographs contributed by Drs. Sunil Balgobin, Manisha Sharma, Rebecca Stone.)

Treatment standards are lacking, and several options are available. Hysterectomy is an acceptable initial choice in those desiring sterilization. It is sometimes a necessary option with heavy uncontrolled bleeding. Fertility-preserving options include systemic or locally injected methotrexate, either alone or combined with conservative surgery (Shen, 2012; Timor-Tritsch, 2012b; Yang, 2010). Surgeries include visually guided suction curettage or transvaginal aspiration, hysteroscopic removal, or isthmic excision. These are completed solely or more typically with adjunctive methotrexate (Michener, 2009; Seow, 2004, 2013; Timor-Tritsch, 2012a; Wang, 2009, 2012; Yang, 2009). Often uterine artery embolization is used preoperatively to minimize hemorrhage risk (Zhang, 2012; Zhuang, 2009).

OTHER SITES OF ECTOPIC PREGNANCY

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, intramural uterine implantations at sites other than a cesarean scar have been noted in women with prior uterine surgeries, ART, or adenomyosis (Memtsa, 2013; Wu, 2013). Although laparotomy is preferred by many for these ectopic sites, laparoscopic excision in hemodynamically stable patients by those with suitable skills is gaining acceptance.

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