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• W2092135967 abstract "Over the past 20 years, a substantial body of research has accumulated about ectopic pregnancy, especially about its epidemiology, risk factors, and diagnosis. Nonetheless, the care of women with these pregnancies remains a topic of debate, and no consensus or guidelines exist to clarify the optimal treatment choices. This review revisits the four primary treatments for ectopic pregnancy and defines and details the concept of “activity,” which guides the indications for each treatment. Recent findings of no difference in fertility during the 2 years after an ectopic pregnancy have answered some old questions and raised new ones for determining the optimal management of ectopic pregnancies. Most especially, they allow the consideration and weighing of a wider range of factors, including the woman's own preferences as well as efficacy and the monitoring time until recovery. Over the past 20 years, a substantial body of research has accumulated about ectopic pregnancy, especially about its epidemiology, risk factors, and diagnosis. Nonetheless, the care of women with these pregnancies remains a topic of debate, and no consensus or guidelines exist to clarify the optimal treatment choices. This review revisits the four primary treatments for ectopic pregnancy and defines and details the concept of “activity,” which guides the indications for each treatment. Recent findings of no difference in fertility during the 2 years after an ectopic pregnancy have answered some old questions and raised new ones for determining the optimal management of ectopic pregnancies. Most especially, they allow the consideration and weighing of a wider range of factors, including the woman's own preferences as well as efficacy and the monitoring time until recovery. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/capmasp-ectopic-pregnancy-methotrexate/ Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/capmasp-ectopic-pregnancy-methotrexate/ The past 20 years have seen the accumulation of a substantial body of information about ectopic pregnancies, especially about their epidemiology (1Farquhar C.M. Ectopic pregnancy.Lancet. 2005; 366: 583-591Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar, 2Skjeldestad F.E. Hadgu A. Eriksson N. Epidemiology of repeat ectopic pregnancy: a population-based prospective cohort study.Obstet Gynecol. 1998; 91: 129-135Crossref PubMed Scopus (42) Google Scholar, 3Ankum W.M. Is the rising incidence of ectopic pregnancy unexplained?.Human Reprod. 1996; 11: 238-239Crossref PubMed Scopus (8) Google Scholar, 4Bakken I.J. Skjeldestad F.E. Time trends in ectopic pregnancies in a Norwegian county 1970–2004—a population-based study.Hum Reprod. 2006; 21: 3132-3136Crossref PubMed Scopus (23) Google Scholar, 5Van Den Eeden S.K. Shan J. Bruce C. Glasser M. Ectopic pregnancy rate and treatment utilization in a large managed care organization.Obstet Gynecol. 2005; 105: 1052-1057Crossref PubMed Scopus (111) Google Scholar, 6Ectopic pregnancy—United States, 1970–1992.MMWR Morb Mortal Wkly Rep. 1995; 44: 46-48PubMed Google Scholar, 7Butts S. Sammel M. Hummel A. Chittams J. Barnhart K. Risk factors and clinical features of recurrent ectopic pregnancy: a case control study.Fertil Steril. 2003; 80: 1340-1344Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), risk factors (8Tay J.I. Moore J. Walker J.J. Ectopic pregnancy.BMJ. 2000; 320: 916-919Crossref PubMed Google Scholar, 9Coste J. Bouyer J. Job-Spira N. Maternal life events and adverse pregnancy outcomes: lessons from the Auvergne ectopic pregnancy registry.Fertil Steril. 2004; 81: 137-148Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 10Bouyer J. Coste J. Shojaei T. Pouly J.L. Fernandez H. Gerbaud L. et al.Risk factors for ectopic pregnancy: a comprehensive analysis based on a large case control population-based study in France.Am J Epidemiol. 2003; 157: 185-194Crossref PubMed Scopus (293) Google Scholar, 11Coste J. Fernandez H. Joye N. Benifla J. Girard S. Marpeau L. et al.Role of chromosome abnormalities in ectopic pregnancy.Fertil Steril. 2000; 74: 1259-1260Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 12Bouyer J. Rachou E. Germain E. Fernandez H. Coste J. Pouly J.L. et al.Risk factors for extrauterine pregnancy in women using an intrauterine device.Fertil Steril. 2000; 74: 899-908Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 13Saraiya M. Berg D.J. Kendrick J.S. Strauss L.T. Atrash H.K. Ahn Y.W. Cigarette smoking as a risk factor for ectopic pregnancy.Am J Obstet Gynecol. 1998; 178: 493-498Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 14Zhang J. Thomas G. Leybovich E. Vaginal douching and adverse health effects: a meta-analysis.Am J Public Health. 1997; 87: 1207-1211Crossref PubMed Google Scholar, 15Parazzini F. Oestrogens and progesterone concentrations and risk of ectopic pregnancy: an epidemiological point of view.Human Reprod. 1996; 11: 236-238Crossref PubMed Scopus (7) Google Scholar, 16Ankum W.M. Mol B.W. Van der Veen F. Risk factors for ectopic pregnancy: a meta analysis.Fertil Steril. 1996; 65: 1093-1099Abstract Full Text PDF PubMed Google Scholar, 17Parazzini F. Ferraroni M. Tozzi L. Benzi G. Rossi G. La Vecchia C. Past contraceptive method use and risk of ectopic pregnancy.Contraception. 1995; 52: 93-98Abstract Full Text PDF PubMed Scopus (12) Google Scholar, 18Mol B.W. Ankum W.M. Bossuyt P.M. Van der Veen F. Contraception and the risk of ectopic pregnancy: a meta-analysis.Contraception. 1995; 52: 337-341Abstract Full Text PDF PubMed Scopus (87) Google Scholar), and diagnosis (19Butts S. Sammel M. Hummel A. Chittams J. Barnhart K. Risk factors and clinical features of recurrent ectopic pregnancy: a case control study.Fertil Steril. 2003; 80: 1340-1344Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 20Pisarska M.D. Carson S.A. Buster J.E. Ectopic pregnancy.Lancet. 1998; 351: 1115-1120Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 21Coste J. Bouyer J. Job-Spira N. Construction of composite scales for risk assessment in epidemiology: an application to ectopic pregnancy.Am J Epidemiol. 1997; 145: 278-289Crossref PubMed Scopus (28) Google Scholar, 22Mol B.W. Hajenius P.J. Engelsbel S. Ankum W.M. van der Veen F. Hemrika D.J. et al.Are gestational age and endometrial thickness alternatives for serum human chorionic gonadotropin as criteria for the diagnosis of ectopic pregnancy?.Fertil Steril. 1999; 72: 643-645Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 23van Mello N.M. Mol F. Ankum W.M. Mol B.W. van der Veen F. Hajenius P.J. Ectopic pregnancy: how the diagnostic and therapeutic management has changed.Fertil Steril. 2012; 98: 1066-1073Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Nonetheless, the care of women with these pregnancies remains a topic of debate, and no consensus or guidelines exist to clarify the choice between different treatments (1Farquhar C.M. Ectopic pregnancy.Lancet. 2005; 366: 583-591Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar). Moreover, medical treatment is subject to substantial variation, including differing protocols and varying routes of administration. In developing countries, ectopic pregnancy is a potentially life-threatening condition, and in developed countries, it is still a leading cause of maternal mortality. However, earlier diagnosis and better access to care have shifted concern to the issues of preserving subsequent fertility, the woman's own preferences, and cost considerations. In particular, the recent reports about subsequent fertility (24de Bennetot M. Rabischong B. Aublet-Cuvelier B. Belard F. Fernandez H. Bouyer J. et al.Fertility after tubal ectopic pregnancy: results of a population-based study.Fertil Steril. 2012; 98: 1271-1276.e1–3Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 25Fernandez H. Capmas P. Lucot J.P. Resch B. Panel P. Bouyer J. Fertility after ectopic pregnancy: the DEMETER randomized trial.Hum Reprod. 2013; 28: 1247-1253Crossref PubMed Scopus (104) Google Scholar) must be integrated into any guidelines for the management of ectopic pregnancy. This review first defines and details the concept of activity, which guides the indication for each treatment. We then describe the four primary treatments, and discuss the factors that aid in choosing which treatment is appropriate. An ectopic pregnancy's level of activity is the major factor in deciding the most appropriate treatment. This concept is well recognized and generally applied as a guideline for determining which ectopic pregnancies may benefit from medical treatment. Nonetheless, the definition of activity remains a subject of debate. The most active ectopic pregnancies have a high risk of tubal rupture or have already ruptured. In such cases, medical treatment cannot be attempted because of the high risk of failure. These ectopic pregnancies include those with hemodynamic failure, with abundant hemoperitoneum, with symptoms of rupture (such as pain and syncope), or with a high human chorionic gonadotropin (hCG) level (for which the threshold level is the subject of further debate). The consensus about the management of these ectopic pregnancies is that they require a surgical approach. For other situations, the criteria for defining active and less active ectopic pregnancies and the cut-off line between them are controversial. Some studies have used scores, such as those of Fernandez et al. (25Fernandez H. Capmas P. Lucot J.P. Resch B. Panel P. Bouyer J. Fertility after ectopic pregnancy: the DEMETER randomized trial.Hum Reprod. 2013; 28: 1247-1253Crossref PubMed Scopus (104) Google Scholar), who measured including pain, time of amenorrhea, hCG and progesterone level, size of hematosalpinx, and importance of hemoperitoneum; and Elito et al. (26Elito J. Reichmann A.P. Uchiyama M.N. Camano L. Predictive score for the systemic treatment of unruptured ectopic pregnancy with a single dose of methotrexate.Int J Gynaecol Obstet. 1999; 67: 75-79Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar), who measured the hCG level and the size of the mass, and emphasized the sonographic aspects (live embryo, tubal ring, or hematosalpinx) and the importance of color Doppler. Others have reported on sonographic findings: the size of the hematosalpinx, or the presence of a yolk sac, an embryo, or cardiac activity (28Bixby S. Tello R. Kuligowska E. Presence of a yolk sac on transvaginal sonography is the most reliable predictor of single-dose methotrexate treatment failure in ectopic pregnancy.J Ultrasound Med. 2005; 24: 591-598PubMed Google Scholar, 29da Costa Soares R. Elito J. Camano L. Increment in beta-hCG in the 48-h period prior to treatment: a new variable predictive of therapeutic success in the treatment of ectopic pregnancy with methotrexate.Arch Gynecol Obstet. 2008; 278: 319-324Crossref PubMed Scopus (23) Google Scholar, 30Dilbaz S. Caliskan E. Dilbaz B. Degirmenci O. Haberal A. Predictors of methotrexate treatment failure in ectopic pregnancy.J Reprod Med. 2006; 51: 87-93PubMed Google Scholar, 31Nazac A. Gervaise A. Bouyer J. de Tayrac R. Capella-Allouc S. Fernandez H. Predictors of success in methotrexate treatment of women with unruptured tubal pregnancies.Ultrasound Obstet Gynecol. 2003; 21: 181-185Crossref PubMed Scopus (57) Google Scholar, 32Nowak-Markwitz E. Michalak M. Olejnik M. Spaczynski M. Cutoff value of human chorionic gonadotropin in relation to the number of methotrexate cycles in the successful treatment of ectopic pregnancy.Fertil Steril. 2009; 92: 1203-1207Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 33Tawfiq A. Agameya A.F. Claman P. Predictors of treatment failure for ectopic pregnancy treated with single-dose methotrexate.Fertil Steril. 2000; 74: 877-880Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 34Moon M.H. Lee Y.H. Lim K.T. Yang J.H. Park S.H. Outcome prediction for treatment of tubal pregnancy using an intramuscular methotrexate protocol.J Ultrasound Med. 2008; 27: 1461-1467PubMed Google Scholar, 35Menon S. Colins J. Barnhart K.T. Establishing a human chorionic gonadotropin cutoff to guide methotrexate treatment of ectopic pregnancy: a systematic review.Fertil Steril. 2007; 87: 481-484Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). Most studies have recommended measuring the pretreatment serum hCG level (36Lipscomb G.H. Puckett K.J. Bran D. Ling F.W. Management of separation pain after single-dose methotrexate therapy for ectopic pregnancy.Obstet Gynecol. 1999; 93: 590-593Crossref PubMed Scopus (47) Google Scholar). The cut-off for defining a less active—that is, medically treatable—pregnancy varies from 1,500 to 5,000 IU/L (29da Costa Soares R. Elito J. Camano L. Increment in beta-hCG in the 48-h period prior to treatment: a new variable predictive of therapeutic success in the treatment of ectopic pregnancy with methotrexate.Arch Gynecol Obstet. 2008; 278: 319-324Crossref PubMed Scopus (23) Google Scholar, 32Nowak-Markwitz E. Michalak M. Olejnik M. Spaczynski M. Cutoff value of human chorionic gonadotropin in relation to the number of methotrexate cycles in the successful treatment of ectopic pregnancy.Fertil Steril. 2009; 92: 1203-1207Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 33Tawfiq A. Agameya A.F. Claman P. Predictors of treatment failure for ectopic pregnancy treated with single-dose methotrexate.Fertil Steril. 2000; 74: 877-880Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 34Moon M.H. Lee Y.H. Lim K.T. Yang J.H. Park S.H. Outcome prediction for treatment of tubal pregnancy using an intramuscular methotrexate protocol.J Ultrasound Med. 2008; 27: 1461-1467PubMed Google Scholar, 35Menon S. Colins J. Barnhart K.T. Establishing a human chorionic gonadotropin cutoff to guide methotrexate treatment of ectopic pregnancy: a systematic review.Fertil Steril. 2007; 87: 481-484Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar), although the latter (higher) threshold appears to be the more frequently used by recent studies. The progesterone level is also included in the scoring of Fernandez et al. (27Fernandez H. Lelaidier C. Thouvenez V. Frydman R. The use of a pretherapeutic, predictive score to determine inclusion criteria for the non-surgical treatment of ectopic pregnancy.Hum Reprod. 1991; 6: 995-998PubMed Google Scholar). However, no studies have reported their results using this concentration as a marker of the activity of ectopic pregnancies, and no cut-off value has been demonstrated. A threshold of 10 ng/mL is the most commonly used (27Fernandez H. Lelaidier C. Thouvenez V. Frydman R. The use of a pretherapeutic, predictive score to determine inclusion criteria for the non-surgical treatment of ectopic pregnancy.Hum Reprod. 1991; 6: 995-998PubMed Google Scholar, 37Rozenberg P. Chevret S. Camus E. de Tayrac R. Garbin O. de Poncheville L. et al.Medical treatment of ectopic pregnancies: a randomized clinical trial comparing methotrexate-mifepristone and methotrexate-placebo.Hum Reprod. 2003; 18: 1802-1808Crossref PubMed Scopus (58) Google Scholar, 38Carson S.A. Buster J.E. Ectopic pregnancy.N Engl J Med. 1993; 329: 1174-1181Crossref PubMed Scopus (0) Google Scholar). Because progesterone levels are still not sufficiently evaluated or used to define activity, the use of a single parameter such as hCG level is probably easier for current practice and for comparing studies. In conclusion, we propose to define a less active ectopic pregnancy, that is, one that can be treated medically, with a pretreatment serum hCG level <5,000 IU/L, with no cardiac activity in the embryo, in a woman with no symptoms who is hemodynamically stable. It might also be useful to define a very inactive ectopic pregnancy or pregnancies of unknown location (PUL) as those with low (<1,500 IU/L) and plateauing serum hCG concentrations. Monitoring until recovery is a good option for some ectopic pregnancies as for PUL. Like intrauterine pregnancies, ectopic pregnancies can resolve spontaneously. Expectant management consists of monitoring the woman until recovery (i.e., until the hCG level drops below 2 IU/L). The follow-up evaluation must be intensive: every other day at the beginning and then weekly until the hCG level returns to normal. Tanaka et al. (39Tanaka T. Hayashi H. Kutsuzawa T. Fujimoto S. Ichinoe K. Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case.Fertil Steril. 1982; 37: 851-852Abstract Full Text PDF PubMed Scopus (367) Google Scholar) reported the first use of methotrexate as medical treatment for ectopic pregnancy in 1982. Methotrexate is an antimetabolite that acts on actively proliferating cells, including trophoblastic tissue. The dose of methotrexate used in ectopic pregnancy is 1 mg/kg or 50 mg/m2. There are different protocols for methotrexate injections. The single-dose methotrexate regimen allows for reinjection at the same dose if needed—that is, should the hCG level not decrease sufficiently (day 7 hCG > initial hCG rate, or subsequent decreases <15% each week) (40Stovall T.G. Ling F.W. Ectopic pregnancy: diagnostic and therapeutic algorithms minimizing surgical intervention.J Reprod Med. 1993; 38: 807-812PubMed Google Scholar). For the two-dose methotrexate regimen, the first injection is administered on day 0, and a second injection of the same dose is administered on day 4 (41Barnhart K. Hummel A.C. Sammel M.D. Menon S. Jain J. Chakhtoura N. Use of “2- dose” regimen of methotrexate to treat ectopic pregnancy.Fertil Steril. 2007; 87: 250-256Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). The fixed multidose methotrexate regimen consists of four injections of the same dose on days 1, 3, 5, and 7, with administration of folinic acid (0.1 mg/kg) on days 2, 4, 6, and 8. In situ injection of methotrexate with sonographic guidance is often used for extratubal ectopic pregnancies (42Jermy K. Thomas J. Doo A. Bourne T. The conservative management of interstitial pregnancy.BJOG. 2004; 111: 1283-1288Crossref PubMed Scopus (120) Google Scholar, 43Fernandez H. Benifla J.L. Madelenat P. Medical treatment of cornual pregnancy?.Fertil Steril. 1996; 66: 862PubMed Google Scholar, 44Lau S. Tulandi T. Conservative medical and surgical management of interstitial ectopic pregnancy.Fertil Steril. 1999; 72: 207-215Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 45Kirk E. Bourne T. The nonsurgical management of ectopic pregnancy.Curr Opin Obstet Gynecol. 2006; 18: 587-593Crossref PubMed Scopus (34) Google Scholar) but may also be used for tubal pregnancies. The addition of folinic acid to methotrexate therapy has not been found to provide any advantages: the half-life of methotrexate is very short, and even with the four-injection protocol the methotrexate dose is very low compared with the levels used in rheumatology or oncology (46Bourget P. Fernandez H. Quinquis-Desmaris V. Pharmacological treatment of ectopic pregnancy [article in French].Therapie. 1993; 48: 215-223PubMed Google Scholar). Hyperosmolar glucose has also been injected into the fallopian tube under sonographic guidance to resolve ectopic pregnancies. Although it has been replaced by methotrexate as a general rule, it is often still used in heterotopic pregnancies when the use of methotrexate is contraindicated (47Timor-Tritsch I.E. Hyperosmolar glucose injection for the treatment of heterotopic ovarian pregnancy.Obstet Gynecol. 2012; 120: 1212-1213PubMed Google Scholar, 48Allison J.L. Aubuchon M. Leasure J.D. Schust D.J. Hyperosmolar glucose injection for the treatment of heterotopic ovarian pregnancy.Obstet Gynecol. 2012; 120: 449-452Crossref PubMed Google Scholar, 49Raughley M.J. Frishman G.N. Local treatment of ectopic pregnancy.Semin Reprod Med. 2007; 25: 99-115Crossref PubMed Scopus (19) Google Scholar, 50Lang P.F. Weiss P.A. Mayer H.O. Haas J.G. Honigl W. Conservative treatment of ectopic pregnancy with local injection of hyperosmolar glucose solution or prostaglandin-F2 alpha: a prospective randomised study.Lancet. 1990; 336: 78-81Abstract PubMed Scopus (72) Google Scholar). Currently, salpingotomy is performed by laparoscopy whenever possible. The procedure calls for the introduction of a 10-mm (or less) laparoscope through the umbilicus, and the insertion of two 5-mm (or less) ports in the left and right hypochondriac regions. A 10-mm (but not less) suprapubic trocar is then inserted, and a monopolar linear incision is made over the bulging antimesenteric portion of the tube. A 10-mm irrigation probe for hydrodissection is then used to remove the ectopic mass. The irrigation probe must be 10 mm to be able to remove completely the ectopic pregnancy; the only reported cohort with a <7% failure rate with conservative surgery used a 10-mm irrigation probe (51Rabischong B. Predicting success of laparoscopic salpingostomy for ectopic pregnancy.Obstet Gynecol. 2010; 116: 701-707Crossref PubMed Scopus (17) Google Scholar). Hemostasis must be obtained without extended coagulation to preserve a functional tube. The tubal incision is left open to allow secondary healing, and the pelvis is irrigated (51Rabischong B. Predicting success of laparoscopic salpingostomy for ectopic pregnancy.Obstet Gynecol. 2010; 116: 701-707Crossref PubMed Scopus (17) Google Scholar). The major disadvantage of conservative surgery is the risk of persistent trophoblast cells. One well-designed randomized trial suggested that routine prophylactic postoperative injection of methotrexate reduces this risk (52Graczykowski J.W. Mishell D.R. Methotrexate prophylaxis for persistent ectopic pregnancy after conservative treatment by salpingostomy.Obstet Gynecol. 1997; 89: 118-122Crossref PubMed Scopus (100) Google Scholar). Salpingectomy is generally performed by laparoscopy. The standard protocol calls for a 10-mm (or less) laparoscope to be introduced through the umbilicus and three 5-mm (or less) ports inserted in the left and the right hypochondriac and suprapubic regions. Salpingectomy involves the removal of the fallopian tube with the products of pregnancy inside it, either from the horn to the fimbrial portion (anterograde) or from the fimbrial portion to the horn (retrograde). It is performed by stepwise dissection of the mesosalpinx and fallopian tube with bipolar electrocautery forceps and scissors. The salpinx is then removed from the abdominal cavity in a specimen bag to avoid dissemination of trophoblasts. Methotrexate should not be used as the first-line therapy for very inactive ectopic pregnancies (or PULs); expectant management should be preferred. The earliest data about expectant management come from a retrospective study published in 1955, but many studies have been conducted since then (53Banerjee S. Aslam N. Woelfer B. Lawrence A. Elson J. Jurkovic D. Expectant management of early pregnancies of unknown location: a prospective evaluation of methods to predict spontaneous resolution of pregnancy.BJOG. 2001; 108: 158-163PubMed Google Scholar, 54Elson J. Tailor A. Banerjee S. Salim R. Hillaby K. Jukovic D. Expectant management of tubal ectopic pregnancy: prediction of successful outcome using decision tree analysis.Ultrasound Obstet Gynecol. 2004; 23: 552-556Crossref PubMed Scopus (102) Google Scholar, 55Kirk E. Van Calster B. Condous G. Papageorghiou A.T. Gevaert O. Van Huffel S. et al.Ectopic pregnancy: using the hCG ratio to select women for expectant or medical management.Acta Obstet Gynecol Scand. 2011; 90: 264-272PubMed Google Scholar). A favorable outcome can be anticipated with expectant management in 20% of ectopic pregnancies, regardless of their activity level. A recent randomized trial (the METEX trial) compared methotrexate with expectant management in women with an ectopic pregnancy or PUL who had low and plateauing serum hCG concentrations. This multicenter trial, which included 73 women over a 5-year period (41 with single-dose methotrexate, and 32 with expectant management), found no difference in the uneventful decline of serum hCG to undetectable levels: 76% after methotrexate treatment, and 59% after expectant management, relative risk 1.3 (95% confidence interval [CI], 0.9–1.8) (56van Mello N.M. Mol F. Verhoeve H.R. van Wely M. Adriaansa A.H. Boss E.A. et al.Methotrexate or expectant management in women with an ectopic pregnancy or pregnancy of unknown location and low serum hCG concentrations? A randomized comparison.Hum Reprod. 2013; 28: 60-67Crossref PubMed Scopus (85) Google Scholar). A nonsignificant trend was found, which could have been improved by more power. The METEX trial results showed that methotrexate should be used only as a second-line therapy in very less active ectopic pregnancies. Although measurement of progesterone levels may contribute to confirming a very less active ectopic pregnancy, it cannot be recommended because the METEX study did not measure progesterone levels, and there are no published data for progesterone in very less active ectopic pregnancies. Medical treatment by methotrexate should be used only in less active pregnancies; otherwise, the risk of failure is high. In the absence of contraindications, which include abnormal baseline liver and renal function test results, medical management can be chosen after the woman has been informed about the method of treatment, the risk of failure, and the necessity of follow-up observation. All three previously described injection protocols can be used. The reported success rates of methotrexate therapy range from 63% to 96.7%. The heterogeneity of these results is due to variations in patient characteristics, in study inclusion criteria, in pretreatment hCG levels (see the definition of less active ectopic pregnancy), and in methotrexate treatment protocols (see the definition of treatment) as well as the different definitions of treatment failure. Some studies, for example, considered treatment failures to be only cases that finally required surgery (25Fernandez H. Capmas P. Lucot J.P. Resch B. Panel P. Bouyer J. Fertility after ectopic pregnancy: the DEMETER randomized trial.Hum Reprod. 2013; 28: 1247-1253Crossref PubMed Scopus (104) Google Scholar, 57Fernandez H. Yves Vincent S.C. Pauthier S. Audibert F. Frydman R. Randomized trial of conservative laparoscopic treatment and methotrexate administration in ectopic pregnancy and subsequent fertility.Hum Reprod. 1998; 13: 3239-3243Crossref PubMed Scopus (124) Google Scholar, 58Hajenius P.J. Engelsbal S. Mol B.W. Van der Veen F. Ankul W.M. Bossuyt P.M. et al.Randomised trial of systemic methotrexate versus laparoscopic salpingostomy in tubal pregnancy.Lancet. 1997; 350: 774-779Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar); other studies defined failure as the need for a supplementary methotrexate injection (59Sowter M.C. Farquhar C.M. Petrie K.J. Gudex G. A randomised trial comparing single dose systemic methotrexate and laparoscopic surgery for the treatment of unruptured tubal pregnancy.BJOG. 2001; 108: 192-203PubMed Google Scholar). In the DEMETER multicentre trial, 207 women were included in the arm comparing medical management with conservative surgery, and the reported success rate for methotrexate in 110 women was 75% (25Fernandez H. Capmas P. Lucot J.P. Resch B. Panel P. Bouyer J. Fertility after ectopic pregnancy: the DEMETER randomized trial.Hum Reprod. 2013; 28: 1247-1253Crossref PubMed Scopus (104) Google Scholar). Very few studies have reported on the use of in situ injection of methotrexate for tubal ectopic pregnancies, although it is often used for nontubal ectopic pregnancies (such as interstitial, cervical, or cesarean scar) (42Jermy K. Thomas J. Doo A. Bourne T. The conservative management of interstitial pregnancy.BJOG. 2004; 111: 1283-1288Crossref PubMed Scopus (120) Google Scholar, 43Fernandez H. Benifla J.L. Madelenat P. Medical treatment of cornual pregnancy?.Fertil Steril. 1996; 66: 862PubMed Google Scholar, 44Lau S. Tulandi T. Conservative medical and surgical management of interstitial ectopic pregnancy.Fertil Steril. 1999; 72: 207-215Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 45Kirk E. Bourne T. The nonsurgical management of ectopic pregnancy.Curr Opin Obstet Gynecol. 2006; 18: 587-593Crossref PubMed Scopus (34) Google Scholar). A retrospective study by Nazac et al. (31Nazac A. Gervaise A. Bouyer J. de Tayrac R. Capella-Allouc S. Fernandez H. Predictors of success in methotrexate treatment of women with unruptured tubal pregnancies.Ultrasound Obstet Gynecol. 2003; 21: 181-185Crossref PubMed Scopus (57) Google Scholar) reported a success rate of 90% with tubal ectopic pregnancies, which is significantly better than the results with intramuscular injections. This route of administration should be explored further in a randomized trial. Conservative surgery, generally considered the standard treatment in less active ectopic pregnancies (60Vermesh M. Conservative management of ectopic gestation.Fertil Steril. 1989; 51: 559-567Abstract Full Text PDF PubMed Scopus (67) Google Scholar, 61Vermesh M. Silva P.D. Rosen G.F. Stein A.L. Fossum G.T. Sauer M.V. Management of unruptured ectopic gestation by linear salpingostomy: a prospective, randomized clinical trial of laparoscopy versus laparotomy.Obstet Gynecol. 1989; 73: 400-404PubMed Google Scholar, 62Mol F. Mol B.W. Ankum W.M. van der Veen F. Hajenius P.J. Current evidence on surgery, systemic methotrexate and expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis.Hum Reprod Update. 2008; 14: 309-319Crossr" @default.
• W2092135967 created "2016-06-24" @default.
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• W2092135967 date "2014-03-01" @default.
• W2092135967 modified "2023-10-18" @default.
• W2092135967 title "Treatment of ectopic pregnancies in 2014: new answers to some old questions" @default.
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