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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.
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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.
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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.
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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).
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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).
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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).
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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.
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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).
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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).
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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.
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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.
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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.
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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.
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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.
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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).
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Other Medical Options
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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.
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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).
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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).
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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.
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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).
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Laparotomy versus Laparoscopy
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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.
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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).
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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).
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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).
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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.
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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.
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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).
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Medical versus Surgical Therapy
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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).
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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).
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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.
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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.
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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.
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Persistent Ectopic Pregnancy
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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.
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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.
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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.