1.Medical treatment of ectopic pregnancy The Practice Committee of the American Society for Reproductive MedicineAmerican Society for Reproductive Medicine, Birmingham, AlabamaAppropriate use of medical therapy of early ectopic pregnancies is discussed. (Fertil Steril 2008;90:S20612.2008 by American Society for Reproductive Medicine.)Ectopic pregnancy is a signicant cause of morbidity and ment. Diagnosis of all women at risk for ectopic pregnancymortality in the rst trimester of pregnancy (1). Currently, should be prompt but is not always an emergency. Any repro-a high index of suspicion, serial hormone assays, and transva- ductive age woman experiencing abnormal vaginal bleedingginal ultrasonography (TVU) facilitate the diagnosis and with or without abdominal pain is at risk for ectopic preg-treatment of ectopic pregnancy before rupture occurs. Earlynancy. Such women should be followed closely until a diag-nonsurgical diagnosis and timely treatment have resulted innosis is made. Given the high risk of recurrence, women witha dramatic decline in mortality due to ectopic pregnancy (1).history of a previous ectopic pregnancy should be followed carefully, even in the absence of symptoms. A hemodynam- Treatment with methotrexate (MTX), a folic acid antago- ically stable woman at risk for an ectopic pregnancy shouldnist highly toxic to rapidly replicating tissues, now reportedly be diagnosed before rupture, a goal that often can be accom-achieves results comparable to surgery for the treatment of plished without laparoscopy. For women who present inappropriately selected ectopic pregnancies and is used com- shock, immediate surgery is both diagnostic and therapeutic.monly (2). An unruptured ectopic pregnancy can be managedwith either surgery or methotrexate. Surgery is specically Diagnostic approaches that use serial hCG, ultrasono-indicated in cases of suspected tubal rupture and when graphic examinations, and sometimes uterine curettage facil-MTX is contraindicated.itate the early diagnosis of ectopic pregnancy (911). A gestational sac (or sacs) should become visible by TVU be-PREVALENCE tween 5.5 and 6.0 weeks gestational age (12, 13). In se-There are more than 100,000 ectopic pregnancies reported quence, structures such as a gestational sac (doubleper year in the United States, but the actual number is almost decidual sign), yolk sac, and fetal pole with later cardiaccertainly much greater because only cases managed surgi- motion become visible by TVU. When gestational age iscally are reported (3, 4). At least 90% of all ectopic pregnan-not known, hCG levels can provide alternate criteria for tim-cies are located in the fallopian tube, and 80% of those are ing and interpretation of TVU (14, 15).located in the ampullary segment of the tube (5).It now is widely accepted that above the discriminatory zone of 1,500 IU/L2,500 IU/L, a normal intrauterine preg-RISK FACTORS nancy (IUP) should be visible by TVU. The absence of an in-Any pregnant woman can potentially have an ectopic preg- trauterine gestational sac when the hCG concentration isnancy. Damage to the fallopian tubes predisposes a woman above the discriminatory zone implies an abnormal gestation.to ectopic pregnancy. Knowledge of risk factors can help The specic cutoff value for hCG used at each institution willidentify women who may benet from close monitoringdepend on clinical expertise and the specic characteristics ofand early treatment. High-risk conditions include [1] previ- the hCG assay used. A more conservative discriminatoryous ectopic pregnancy; [2] history of tubal surgery, including zone, that is, higher hCG level, may be used to minimizea previous tubal sterilization; [3] history of sexually transmit-the risk of terminating a viable pregnancy (16). In the caseted infection, tubal infection, or pelvic adhesions; [4] current of multiple pregnancy, hCG levels are higher at an early stageuse of an intrauterine device; [5] conception resulting from of development than in singleton intrauterine gestations, butassisted reproduction; [6] cigarette smoking; and [7] in utero the rate of increase remains similar (17).exposure to diethylstilbestrol (68). If the initial hCG level is below the discriminatory zone, and TVU cannot identify denitively an intrauterine or extra-DIAGNOSISuterine gestation, then serial hCG measurements are needed to document either a growing, potentially viable or a nonvia-Timely diagnosis of ectopic pregnancy is important to reduce ble pregnancy. The minimum rise for a potentially viablerisk of rupture and improve the success of medical manage- pregnancy in women who present with symptoms of pain and/or vaginal bleeding is 53% per two days, based on theTechnical BulletinReviewed June 2008. 99th percent condence interval (CI) around the mean ofReceived and accepted September 5, 2006. the curve for b-hCG rise (up to 5,000 IU/L) over time (16).Reprints will not be available.Intervention when the b-hCG level rises less than 66% overS206 Fertility and Sterility Vol. 90, Suppl 3, November 20080015-0282/08/$34.00 Copyright 2008 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2008.08.049

2. 2 days, a practice supported by previous data, potentially may TABLE 1result in the interruption of viable pregnancies (18). When thehCG levels have risen above the discriminatory zone, ultra-Contraindications to MTX therapy (25, 26,sound should be used to document the presence, or absence, 2931).of an IUP. Absolute contraindications Declining hCG values suggest a failing pregnancy. SerialIntrauterine pregnancyhCG levels can be used to show that the gestation is regress-Evidence of immunodeciencying spontaneously. After a complete abortion, hCG levels de- Moderate to severe anemia, leukopenia orcline at least 21%35% every 2 days, depending on the initial thrombocytopeniavalue (19). However, a decline in hCG concentrations at this Sensitivity to MTXrate, or faster, does not exclude entirely the possibility of a re-Active pulmonary diseasesolving ectopic pregnancy or its rupture.Active peptic ulcer disease Clinically important hepatic dysfunction The absence of a gestational sac with an hCG above theClinically important renal dysfunctiondiscriminatory zone, or an abnormally rising or decliningBreast feedinghCG level, suggests an abnormal pregnancy but does not dis-Relative contraindicationstinguish an ectopic pregnancy from a failed intrauterine ges-Embryonic cardiac activity detected bytation. The presumption of an ectopic pregnancy in such transvaginal ultrasonographycircumstances can be incorrect in up to 50% of cases (20). High initial hCG concentration (>5,000A uterine curettage and evaluation of uterine contents maymIU/mL)be helpful to differentiate an abnormal IUP from an ectopicEctopic pregnancy >4 cm in size as imaged bypregnancy (20). Limited endometrial biopsy, such as may transvaginal ultrasonographybe performed with a pipelle suction cannula or similar instru- Refusal to accept blood transfusionment, is insufcient (21, 22). Alternatively, if hCG levelsInability to participate in follow-upcontinue to rise after curettage, the diagnosis of ectopic preg-nancy is established.ASRM Practice Commitee. Treatment of ectopic pregnancy. Fertil Steril 2008. Effort should be made to diagnose ectopic pregnancy de-nitively before medical treatment with MTX. Medical treat-ment for a suspected ectopic pregnancy without a denitivediagnosis does not reduce complication rates or cost because Ideally, a candidate for medical management with MTXmany women with undiagnosed miscarriage would otherwise should meet the following criteria: [1] hemodynamic stabil-be exposed to MTX and its side effects unnecessarily (20, ity, [2] no severe or persistent abdominal pain, [3] commit-23). Potential consequences of medical management of a pre- ment to follow-up until the ectopic pregnancy has resolved,sumed ectopic pregnancy include [1] subsequent pregnanciesand [4] normal baseline liver and renal function tests. Contra-will be viewed as high risk for recurrent ectopic pregnancy indications to MTX treatment are listed in Table 1.resulting in repeated, costly, and anxiety-provoking diagnos- Prior to the rst dose of MTX, women should be screenedtic evaluations; [2] apparent efcacy of MTX to treat ectopicwith a complete blood count, liver function tests, serum cre-pregnancy will be articially increased; and [3] an IUP mayatinine and blood type and Rh. Women having a history ofbe exposed to a known teratogen and abortifacient (2426).pulmonary disease also should have a chest x-ray becauseExposure of a viable pregnancy to MTX may result in embry-of the risk of interstitial pneumonitis in patients with under-opathy, a very serious and avoidable complication that is be-lying lung disease.ing reported with increasing frequency (24). There are two commonly used MTX treatment regimens:multiple dose and single dose. Schema for treatmentand follow-up for the two regimens are summarized in TablesTREATMENT 2 and 3, respectively. The multiple-dose protocol is a regimenMedical treatment protocols for MTX were established in the adapted from early experience with MTX treatment for tro-late 1980s and have become a widely accepted primary treat- phoblastic disease and was the regimen rst used to treat ec-ment for ectopic pregnancy (2731). MTX is a folic acid an- topic pregnancy (27, 28). The multiple-dose protocoltagonist (26, 32). Folic acid normally is reduced toalternates MTX treatment with leucovorin therapy. MTX istetrahydrofolate by the enzyme dihydrofolate reductasecontinued until hCG falls by 15% from its peak concentra-(DHFR), a step in the synthesis of DNA and RNA precursors.tion. Approximately 50% of patients so treated will not re-MTX inhibits DHFR, causing depletion of cofactors requiredquire the full 8-day regimen (29, 30). The term singlefor DNA and RNA synthesis. Folinic acid (leucovorin) is andose actually is a misnomer. Whereas it describes the num-antagonist to MTX that can help reduce otherwise prohibitiveber of MTX injections planned, the regimen includes provi-side effects, particularly when higher doses of MTX are usedsions for additional doses of MTX when the response is(26, 32). inadequate (3335).Fertility and SterilityS207 3. TABLE 2 Multiple-dose MTX treatment protocol (28, 29). Treatment dayLaboratory evaluationIntervention PretreatmenthCG, CBC with differential, liver functionRule out spontaneous Ab tests, creatinine, blood type and Rhogam if Rh negative antibody screen 1 hCG MTX 1.0 mg/kg IM 2 LEU 0.1 mg/kg IM 3 hCG MTX 1.0 mg/kg IM if 15%, stop treatment and startsurveillance 4 LEU 0.1 mg/kg IM 5 hCG MTX 1.0 mg/kg IM if 15%, stop treatment and startsurveillance 6 LEU 0.1 mg/kg IM 7 hCG MTX 1.0 mg/kg IM if 15%, stop treatment and startsurveillance 8 LEU 0.1 mg/kg IM Note: Surveillance every 7 days (until hCG 50%/ Avoid gas-forming foods because they produce 48 hours) before MTX pain.Continued rapid rise in hCG concentrations Avoid new conception until hCG is undetectable.during MTX ASRM Practice Commitee. Treatment of ectopic pregnancy. Fertil Steril 2008. ASRM Practice Commitee. Treatment of ectopic pregnancy. Fertil Steril 2008.incidence of recurrent ectopic pregnancy was a relatively lowconcentrations between 10,000 IU/L and 14,999 IU/L, and13% (29, 31).32% (7/22) when hCG values exceeded 15,000 IU/L (41). An- other observed a 65% (9/17) failure rate for single-dose treat- There have been no randomized trials directly comparing ment with initial hCG levels above 4,000 IU/L (38), and stillthe two different MTX treatment protocols. In a meta-analysis others have reported failure rates of 57% and of 62% when theincluding data from 26 articles and 1,327 cases, the overall initial hCG concentration is over 5,000 IU/L (39, 40). Analy-success rate for MTX treatment was 89% (35). The success sis after combining all published data yields an OR for failurerate of the multiple-dose regimen was 92.7% (95% CI, 89 of 5.45 (95% CI, 3.049.78) when the initial hCG value above96), which was statistically signicantly higher than that 5,000 IU/L compared with that observed when hCG concen-achieved with the single-dose regimen (88.1%; 95% CI, 86 trations are below that threshold. The failure rate for single-90) (35). After controlling for initial hCG values and the pres- dose MTX treatment stratied by initial hCG level is illus-ence of embryonic cardiac activity, the failure rate for single- trated in Figure 1. Because the failure rate rises with the pre-dose therapy was higher than that for multiple-dose treatment treatment hCG concentration, the single-dose MTX treatment(odds ratio 4.75, 95% CI, 1.7712.62) (33). A small random- regimen may be better reserved for patients with a relativelyized clinical trail also noted that single-dose therapy has low initial hCG value (35, 39, 40).a higher failure rate, but the difference was smaller (RR 1.50; 95% CI, 0.445.01) (36). It is possible, but not estab-lished, that the difference in failure rates between the two pro-Treatmenttocols may not be as dramatic in women with an overall goodOverall, MTX is a safe and effective treatment for an unrup-prognosis for successful medical treatment.tured ectopic pregnancy. Very rarely, life-threatening compli- A hybrid protocol, involving two equal doses of MTX (50 cations have been reported with MTX (42, 43). Moremg/m2) administered on days 1 and 4 without leucovorin res-commonly encountered treatment and side effects of MTXcue and follow-up as described previously for the single-doseare listed in Table 6. Some patients develop transient painprotocol, may offer a more optimal balance between conve-(separation pain) between 3 and 7 days after treatment be-nience and efcacy (37). The protocol also allows for more gins (44), but such pain normally resolves within 4 to 12than 2 doses of MTX when hCG values do not decrease15% between days 4 and 7. FIGURE 1Regardless which protocol is used, physicians and patientsshould be aware of a number of important caveats when using Single-dose MTX treatment failure based on hCGMTX for the treatment of ectopic pregnancy (Table 4). level. 20Failure Rate (%) 15Predictors of MTX FailureThe most commonly identied predictors of MTX treatment10failure are listed in Table 5. Whereas the prognosis for suc- 5cessful medical treatment has been demonstrated repeatedly0to correlate with the initial hCG level, no consensus on53%useful diagnostic tool. Systemic MTX and uterine artery em-over 2 days) after four doses in the multi-dose regimen or af- bolization have been used successfully to treat cervical preg-ter two doses in the single-dose regimen (45). nancy. In the presence of cardiac activity, ectopic pregnancies have also been successfully treated with direct injection ofSerial ultrasonographic examinations after MTX treatment potassium chloride or MTX (54, 55).are unnecessary because ultrasonographic ndings cannotdemonstrate or predict treatment failure, unless evidence ofrecent tubal rupture is observed (46). Ovarian and Abdominal Pregnancies Ovarian and abdominal pregnancies are diagnosed deni-ADJUNCTIVE USE OF MTX tively at the time of surgical exploration. Therefore, MTXA persistent ectopic pregnancy can develop after salpingos-is not a rst- line treatment for this condition.tomy or medical management. Consequently, it is importantto monitor hCG levels until they become undetectable. WhenhCG levels rise or plateau, persistent trophoblastic tissue canbe treated successfully with a single dose of MTX (47). MTXCOST ANALYSISalso can be given immediately after salpingostomy as a pro-Approximately 40% of women diagnosed with an ectopicphylactic measure, especially in circumstances where incom-pregnancy are candidates for medical management (35),plete resection is more likely (47, 48). Risk for persistent and 90% of those can be treated successfully without surgeryectopic pregnancy is increased in very early gestations, those (30, 31). Whereas the costs of surgery and out-patient medi-measuring less than 2 cm in diameter, and when initial hCG cal management vary widely with the treating facility and theconcentrations are relatively high (48). region of the country, many cost-effectiveness analyses have favored MTX therapy. Because medical treatments can be ad- ministered in an ofce setting, MTX is less expensive thanUNUSUAL ECTOPIC PREGNANCIESsurgery. Primary surgical therapy is favored when the likeli-Extratubal ectopic pregnancies make up less than 10% of allhood of failure or morbidity from medical treatment is highectopic pregnancies but are associated with greater morbidityand when the time to resolution is likely to be prolonged.(49). Surgery often is the most appropriate rst-line treatmentSuch cases generally are characterized by high initial hCGin such cases, but multiple-dose MTX also has been usedlevels and/or the presence of embryonic cardiac activityeffectively. (56, 57).S210ASRM Practice Commitee Treatment of ectopic pregnancyVol. 90, Suppl 3, November 2008 6. SUMMARY AND RECOMMENDATIONS9. Stovall TG, Ling FW, Carson SA, Buster JE. Nonsurgical diagnosis andtreatment of tubal pregnancy. Fertil Steril 1990;54:5378. Ectopic pregnancies can be diagnosed at early stages, 10. Barnhart K, Mennuti MT, Benjamin I, Jacobson S, Goodman D,even before symptoms become evident.Coutifaris C. Prompt diagnosis of ectopic pregnancy in an emergency de- Both conservative surgery and medical therapy may bepartment setting. Obstet Gynecol 1994;84:10105.viewed as appropriate rst-line therapy.11. Gracia CR, Barnhart KT. Diagnosing ectopic pregnancy: decision anal- Serial serum hCG determinations, TVU examinations,ysis comparing six strategies. Obstet Gynecol 2001;97:46470.12. Fritz MA, Guo SM. Doubling time of human chorionic gonadotropinand uterine curettage provide the means for early diag- (hCG) in early normal pregnancy: relationship to hCG concentrationnosis.and gestational age. Fertil Steril 1987;47:5849. Success rates and fertility after treatment are compara-13. Timor-Tritsch IE, Yeh MN, Peisner DB, Lesser KB, Slavik TA. The useble for medical therapy and conservative surgical treat-of transvaginal ultrasonography in the diagnosis of ectopic pregnancy.ment. Am J Obstet Gynecol 1989;161:15761.14. Romero R, Kadar N, Copel JA, Jeanty P, DeCherney AH, Hobbins JC. Medical therapy appears more cost-effective than sur- The value of serial human chorionic gonadotropin testing as a diagnosticgery except when the initial hCG level is high and/or tool in ectopic pregnancy. Am J Obstet Gynecol 1986;155:3924.embryonic cardiac activity is observed. 15. Kadar N, Romero R. Observations on the log human chorionic gonado- Multiple-dose MTX treatment has a lower failure ratetropin-time relationship in early pregnancy and its practical implications.than single-dose MTX. Single-dose MTX is sufcientAm J Obstet Gynecol 1987;157:738.16. Barnhart KT, Sammel MD, Rinaudo PF, Zhou L, Hummel AC, Guo W.to treat persistent trophoblastic tissue after salpingos- Symptomatic patients with an early viable intrauterine pregnancy: hCGtomy and ectopic pregnancies associated with low initialcurves redened. Obstet Gynecol 2004;104:505.hCG values. 17. Chung K, Sammel MD, Chalian R, Coutifaris C, Feedman M, Postoperative, prophylactic, single-dose systemic MTX Barnhart KT. Dening the rise of serum HCG in viable pregnanciesmay reduce the incidence of persistent ectopic preg-achieved through use of IVF. Hum Reprod 2006;213:8238.18. Kadar N, Freedman M, Zacher M. Further observations on the doublingnancy after salpingostomy.time of human chorionic gonadotropin in early asymptomatic pregnan- MTX-induced embryopathy is a serious and avoidablecies. Fertil Steril 1990;54:7837.complication that may arise when a viable pregnancy 19. Barnhart K, Sammel MD, Chung K, Zhou L, Hummel AC, Guo W. De-is misdiagnosed as an ectopic pregnancy and exposed cline of serum human chorionic gonadotropin and spontaneous completeto MTX treatment. abortion: dening the normal curve. Obstet Gynecol 2004;104:97581.20. Barnhart KT, Katz I, Hummel A, Gracia CR. Presumed diagnosis of ec-topic pregnancy. Obstet Gynecol 2002;100:50510.Acknowledgments: This report was developed under the direction of the Prac- 21. Barnhart KT, Gracia CR, Reindl B, Wheeler JE. Usefulness of pipelle en-tice Committee of the American Society for Reproductive Medicine as a ser-dometrial biopsy in the diagnosis of women at risk for ectopic pregnancy.vice to its members and other practicing clinicians. While this documentAm J Obstet Gynecol 2003;188:9069.reects appropriate management of a problem encountered in the practice 22. Ries A, Singson P, Bidus M, Barnes JG. Use of the endometrial pi-of reproductive medicine, it is not intended to be the only approved standard pelle in the diagnosis of early abnormal gestations. Fertil Sterilof practice or to dictate an exclusive course of treatment. Other plans of man- 2000;74:5935.agement may be appropriate, taking into account the needs of the individual 23. Ailawadi M, Lorch SA, Barnhart KT. 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