Treatment of ectopic pregnancies in 2014: new answers to some old questions Fernandez, M.D., Ph.D.a,b,c Perrine Capmas, M.D.,a,b,c Jean Bouyer, Ph.D.,b and Herve a cologie Obste trique, Ho ^ pital Bice ^tre, GHU Sud (AP-HP), b Inserm, Centre of Research in Epidemiology and Service de Gyne ^ tre, France Population Health (CESP), and c Faculty of Medicine, University of Paris Sud, Le Kremlin Bice 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 Use your smartphone consideration and weighing of a wider range of factors, including the woman's own preferences to scan this QR code as well as efficacy and the monitoring time until recovery. (Fertil SterilÒ 2014;101:615–20. and connect to the Ó2014 by American Society for Reproductive Medicine.) Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/capmasp-ectopic-pregnancy-methotrexate/ T he past 20 years have seen the accumulation of a substantial body of information about ectopic pregnancies, especially about their epidemiology (1–7), risk factors (8–18), and diagnosis (19–23). 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 (1). 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 is- sues of preserving subsequent fertility, the woman's own preferences, and cost considerations. In particular, the recent reports about subsequent fertility (24, 25) 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. ACTIVITY OF AN ECTOPIC PREGNANCY An ectopic pregnancy's level of activity is the major factor in deciding the most appropriate treatment. This concept is Received November 26, 2013; revised and accepted January 16, 2014. P.C. has nothing to disclose. J.B. has nothing to disclose. H.F. has nothing to disclose. cologie Obste trique, Ho ^ pital Bice ^tre, 78 Reprint requests: Perrine Capmas, M.D., Service de Gyne ne ral Leclerc, 94275 Le Kremlin Bice ^tre, France (E-mail: perrine.capmas@bct. avenue du Ge aphp.fr). Fertility and Sterility® Vol. 101, No. 3, March 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.01.029 VOL. 101 NO. 3 / MARCH 2014 discussion forum for this article now.* * Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace. 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. (25), who measured including pain, time of amenorrhea, hCG and progesterone level, size of hematosalpinx, and importance of 615 VIEWS AND REVIEWS hemoperitoneum; and Elito et al. (26), 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 (28–35). Most studies have recommended measuring the pretreatment serum hCG level (36). The cut-off for defining a less active—that is, medically treatable—pregnancy varies from 1,500 to 5,000 IU/ L (29, 32–35), 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. (27). 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 (27, 37, 38). 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. THE FOUR TREATMENTS FOR ECTOPIC PREGNANCY Expectant Management 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. Medical Treatment with Methotrexate Tanaka et al. (39) 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. Intramuscular 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) (40). 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 (41). 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. 616 In situ injection. In situ injection of methotrexate with sonographic guidance is often used for extratubal ectopic pregnancies (42–45) 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 (46). 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 (47–50). Conservative Surgery (Salpingotomy) 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 (51). 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 (51). Methotrexate as an adjuvant to salpingotomy. 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 (52). Radical Surgery (Salpingectomy) 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. INDICATIONS AND EFFECTIVENESS OF TREATMENTS Very Less Active Ectopic Pregnancies 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 VOL. 101 NO. 3 / MARCH 2014 Fertility and Sterility® published in 1955, but many studies have been conducted since then (53–55). 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) (56). 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 secondline 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. Less Active Ectopic Pregnancy (60–63), has a failure rate that ranges from 6.6% (51) to 17.5% (64). The surgeon's skill and experience may play a major role, but there are no published data to confirm this. The choice between medical management versus conservative surgical treatment depends on the woman's preference and her commitment to follow-up observation until recovery—a longer period after medical management than after surgical treatment (65). It also depends on her desire to preserve her subsequent fertility and on the failure rates of each type of treatment. The failure rate of conservative surgery also differs according to whether a postoperative dose of methotrexate is injected. Whether to routinely use a methotrexate injection is still debated. The risk of side effects after a methotrexate injection led the authors of the Cochrane review (63) to recommend against its systematic use; the adverse effects reported for methotrexate treatment of ectopic pregnancies are mainly asymptomatic elevation of liver enzymes, with rare cases of drug-induced hepatitis (1%). Both a randomized trial and a prospective study found that the cost effectiveness of methotrexate treatment for women of was quite substantial (52, 64). The randomized trial in 129 women showed a statistically significant decrease in persistent trophoblasts: 14.5% in the group with no injection versus 1.9% in the group with a postoperative intramuscular methotrexate injection (P>.05) (52). The prospective study, which used in situ methotrexate injections in 81 women, also observed a statistically significant decrease in persistent trophoblasts: 17.5% versus 0 (P>.05) (64). The DEMETER multicenter trial confirmed the low failure rate with postoperative systematic injection of methotrexate: 0.6% in 198 women (25). The question of whether a systematic postoperative methotrexate injection is safe and cost effective needs a definitive answer, especially given that the injection could simplify the monitoring required. In view of its very low failure rate, only one blood sample for hCG at 1 month would be required rather than weekly monitoring. Medical therapy. 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 (25, 57, 58); other studies defined failure as the need for a supplementary methotrexate injection (59). 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% (25). 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) (42–45). A retrospective study by Nazac et al. (31) 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. Recovery time. Time until recovery after an ectopic pregnancy is defined as the time until the hCG level drops below 2 IU/L. After conservative management, the hCG level must be monitored to be able to diagnose a persistent trophoblast, especially if no postoperative injection of methotrexate was performed. The recovery time varies from 20 to 31 days. After medical treatment, this time is reported to be around 30 days (range: 27 to 33 days) (65, 66). Two randomized studies have reached different conclusions about the comparative time to recovery for surgery and medical treatment: Saraj et al. (65) reported that this period is shorter after surgery (20.2 versus 27.2 days, in a study of 38 women), while Colacurci et al. (66) found no significant difference (33.6 days after surgery versus 31.5 after methotrexate, 30 women). In the DEMETER trial, the recovery time after conservative surgery with a postoperative injection of methotrexate was statistically significantly shorter than after methotrexate alone: 16 versus 30 days (P< .01) (25). The time until a woman recovers from the effects of surgery can also vary, but recovery times from laparoscopic surgery are typically short. Conservative surgery. Conservative surgery, generally considered the standard treatment in less active ectopic pregnancies Cost. A comparison between conservative surgery and medical therapy found a significant reduction in direct costs with VOL. 101 NO. 3 / MARCH 2014 617 VIEWS AND REVIEWS a single-dose systemic methotrexate injection. The indirect costs were reduced only in the subgroup of women who had a pretreatment hCG level below 1,500 IU/L (59). The results from the Auvergne ectopic pregnancy registry also found that a protocol with a single dose of methotrexate was more cost effective than laparoscopic surgery (67). Women's preferences. Few published articles have examined women's preferences among the available treatments for ectopic pregnancy. One study comparing preference for methotrexate versus conservative surgery found that most women preferred the methotrexate treatment, at least initially (68). Opinions changed among some women when the hypothetical tubal patency rate decreased. In contrast, one group of women never preferred systemic methotrexate, even when they were told that tubal patency after methotrexate was 100%: those who disliked taking medications or found the idea of a prolonged treatment duration to be distressing (68). Women's preferences also depend the way the alternative treatment options are presented by the physician, a factor that is difficult to take into account but cannot be ignored. Active Ectopic Pregnancy An active ectopic pregnancy requires surgical treatment. The choice between conservative or radical surgery in these cases depends on the woman's history (a homolateral recurrence indicates the need for radical surgery), the appearance and condition of the contralateral tube, and bleeding. Tubal rupture does not systematically necessitate radical treatment, except when hemostasis proves difficult to achieve. Salpingectomy might well be a better choice than leaving an unhealthy tube in place. The choice between radical and conservative surgery is often made during the procedure. Radical surgery has a 100% efficacy rate. The failure rate for conservative surgery, on the other hand, ranges from 6.6% to 17.5%, and with the addition of a postoperative methotrexate injection, the failure rate ranges from 0 to 2%. Van Mello et al. (69) studied women's preferences for radical or conservative surgery and found that most women preferred avoiding a repeat ectopic pregnancy—thus, choosing radical treatment—to having a higher chance of a future spontaneous intrauterine pregnancy. However, Van Mello et al. (69) showed that the risk of additional treatment by methotrexate in cases of conservative surgery for persistent trophoblasts was acceptable if compensated for by a small rise in the intrauterine pregnancy rate. Finally, women preferred radical to conservative surgery after the risks of recurrence and persistent trophoblasts were explained along with information about the spontaneous intrauterine pregnancy rate. This preference was not related to the risk of persistent trophoblasts or the potential need for a methotrexate injection; women were primarily concerned about the risk of recurrence. SUBSEQUENT FERTILITY As previously mentioned, in developed countries, preservation of future fertility is now an important objective in the 618 treatment of ectopic pregnancies. Until recently, the results for fertility after treatment came only from observational studies. For example, the results of the Auvergne ectopic pregnancy registry suggested that fertility is better after conservative treatment, either medical or surgical (24). As will be discussed, some trials have reported results, but until very recently they lacked adequate statistical power for definitive conclusions. Comparison between Conservative Surgery and Medical Treatment The most recent and thorough results from the Auvergne registry conclude that there is no significant difference in terms of subsequent fertility between the two conservative treatments (24, 70–72). Three randomized trials also concluded that no significant difference exists between them, but these studies were not powerful enough to reach definitive conclusions (57, 73, 74). Similarly, the Cochrane review found insufficient data are available to reach a conclusion about future fertility (63). Recently, however, the DEMETER randomized trial confirmed with sufficient power that there was no significant difference in subsequent 2-year fertility when comparing medical management and conservative surgery: 67% versus 71% intrauterine pregnancies, hazard ratio 0.85 (0.59–1.22; P¼ .37) (25). It should be noted, moreover, that when an ectopic pregnancy is treated with methotrexate there is no need for a waiting period before attempting another pregnancy; although methotrexate is a teratogenic agent, its half-life is very short (46). Comparison between Conservative and Radical Surgery Until the DEMETER trial, there were no prospective data for comparing conservative and radical surgery. The DEMETER trial showed no difference in subsequent 2-year fertility: 70% versus 64% for intrauterine pregnancy, respectively, hazard ratio 1.06 (0.69–1.63; P¼ .78) (25). Nevertheless, it is important to mention that the rate of recurrence for ectopic pregnancies ranges from 6% to 10%, regardless of the treatment option chosen. NEW STRATEGIES Using a selective progesterone receptor modulator (i.e., mifepristone) as an adjuvant for medical therapy has been suggested. A randomized trial showed no benefit from the systematic addition of mifepristone, except perhaps in women with a progesterone level of 10 ng/L or more (37). Use of epidermal growth factor receptor inhibitor should be an interesting treatment to combine with methotrexate in the medical therapy of ectopic pregnancy. Results in vitro on placental cells show an inhibition in placental cell growth. These results were confirmed in vivo in mouse models (two cases), revealing doubled rates of fetal resorption when combining the two drugs (75). In a phase I nonrandomized open study, 12 women with ectopic pregnancy were treated with methotrexate and oral gefitinib (epidermal growth factor receptor blocker) compared with 71 controls treated with VOL. 101 NO. 3 / MARCH 2014 Fertility and Sterility® methotrexate alone. Both median serum hCG levels by day 7 and time to resolution were significantly shorter after combination therapy, although the latter also was commonly associated with minor side effects such as transient diarrhea and rash (76). These new therapeutics are promising but need to be evaluated further. Superselective uterine artery embolization combined with intra-arterial injection of methotrexate (leading to an in situ injection of methotrexate) also has suggested good results (77). 11. 12. 13. 14. CONCLUSION Recent findings of no difference in fertility during the 2 years after an ectopic pregnancy when comparing medical treatment versus conservative surgery and conservative surgery versus radical surgery have answered some longstanding questions and raised new ones for determining the optimal management of ectopic pregnancies. These findings in particular have allowed consideration and weighing of a wider range of factors, including women's preferences, efficacy, and the period of monitoring until recovery. In choosing conservative or radical surgery, it is important to bear in mind that the newer randomized trial results pertain only to 2-year subsequent spontaneous fertility rates; thus, these results should not lead to a broad extension of radical treatment. Radical treatment might have a harmful effect on long-term spontaneous fertility in cases of contralateral recurrence. The good results for expectant management in very inactive ectopic pregnancies, another major finding, should encourage a less interventionist approach to PUL. Finally, the characteristics of the women most likely to benefit from medical treatment remain to be clarified as do the best protocols for medical treatment. A consensus about the indications for medical treatment would make it easier to compare future studies and thus to advance our knowledge of these points. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Farquhar CM. Ectopic pregnancy. Lancet 2005;366:583–91. Skjeldestad FE, Hadgu A, Eriksson N. Epidemiology of repeat ectopic pregnancy: a population-based prospective cohort study. Obstet Gynecol 1998;91:129–35. Ankum WM. Is the rising incidence of ectopic pregnancy unexplained? Human Reprod 1996;11:238–9. Bakken IJ, Skjeldestad FE. Time trends in ectopic pregnancies in a Norwegian county 1970–2004—a population-based study. Hum Reprod 2006;21: 3132–6. Van Den Eeden SK, Shan J, Bruce C, Glasser M. Ectopic pregnancy rate and treatment utilization in a large managed care organization. Obstet Gynecol 2005;105:1052–7. Ectopic pregnancy—United States, 1970–1992. MMWR Morb Mortal Wkly Rep 1995;44:46–8. Butts 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;80:1340–4. Tay JI, Moore J, Walker JJ. Ectopic pregnancy. BMJ 2000;320:916–9. Coste J, Bouyer J, Job-Spira N. Maternal life events and adverse pregnancy outcomes: lessons from the Auvergne ectopic pregnancy registry. Fertil Steril 2004;81:137–48. Bouyer J, Coste J, Shojaei T, Pouly JL, Fernandez H, Gerbaud L, et al. Risk factors for ectopic pregnancy: a comprehensive analysis based on a large case VOL. 101 NO. 3 / MARCH 2014 26. 27. 28. 29. 30. 31. 32. control population-based study in France. Am J Epidemiol 2003;157:185– 94. Coste J, Fernandez H, Joye N, Benifla J, Girard S, Marpeau L, et al. Role of chromosome abnormalities in ectopic pregnancy. Fertil Steril 2000;74: 1259–60. Bouyer J, Rachou E, Germain E, Fernandez H, Coste J, Pouly JL, et al. Risk factors for extrauterine pregnancy in women using an intrauterine device. Fertil Steril 2000;74:899–908. Saraiya M, Berg DJ, Kendrick JS, Strauss LT, Atrash HK, Ahn YW. Cigarette smoking as a risk factor for ectopic pregnancy. Am J Obstet Gynecol 1998;178:493–8. Zhang J, Thomas G, Leybovich E. Vaginal douching and adverse health effects: a meta-analysis. Am J Public Health 1997;87:1207–11. Parazzini F. Oestrogens and progesterone concentrations and risk of ectopic pregnancy: an epidemiological point of view. Human Reprod 1996;11:236–8. Ankum WM, Mol BW, Van der Veen F. Risk factors for ectopic pregnancy: a meta analysis. Fertil Steril 1996;65:1093–9. Parazzini F, Ferraroni M, Tozzi L, Benzi G, Rossi G, La Vecchia C. Past contraceptive method use and risk of ectopic pregnancy. Contraception 1995;52: 93–8. Mol BW, Ankum WM, Bossuyt PM, Van der Veen F. Contraception and the risk of ectopic pregnancy: a meta-analysis. Contraception 1995;52:337–41. Butts 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;80:1340–4. Pisarska MD, Carson SA, Buster JE. Ectopic pregnancy. Lancet 1998;351: 1115–20. Coste J, Bouyer J, Job-Spira N. Construction of composite scales for risk assessment in epidemiology: an application to ectopic pregnancy. Am J Epidemiol 1997;145:278–89. Mol BW, Hajenius PJ, Engelsbel S, Ankum WM, van der Veen F, Hemrika DJ, 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;72:643–5. van Mello NM, Mol F, Ankum WM, Mol BW, van der Veen F, Hajenius PJ. Ectopic pregnancy: how the diagnostic and therapeutic management has changed. Fertil Steril 2012;98:1066–73. de 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.e1–3. Fernandez H, Capmas P, Lucot JP, Resch B, Panel P, Bouyer J. Fertility after ectopic pregnancy: the DEMETER randomized trial. Hum Reprod 2013;28: 1247–53. Elito J, Reichmann AP, Uchiyama MN, Camano L. Predictive score for the systemic treatment of unruptured ectopic pregnancy with a single dose of methotrexate. Int J Gynaecol Obstet 1999;67:75–9. Fernandez 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;6:995–8. Bixby 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;24:591–8. da 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;278:319–24. Dilbaz S, Caliskan E, Dilbaz B, Degirmenci O, Haberal A. Predictors of methotrexate treatment failure in ectopic pregnancy. J Reprod Med 2006;51:87–93. Nazac 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: 181–5. Nowak-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; 92:1203–7. 619 VIEWS AND REVIEWS 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 620 Tawfiq A, Agameya AF, Claman P. Predictors of treatment failure for ectopic pregnancy treated with single-dose methotrexate. Fertil Steril 2000;74:877–80. Moon MH, Lee YH, Lim KT, Yang JH, Park SH. Outcome prediction for treatment of tubal pregnancy using an intramuscular methotrexate protocol. J Ultrasound Med 2008;27:1461–7. Menon S, Colins J, Barnhart KT. Establishing a human chorionic gonadotropin cutoff to guide methotrexate treatment of ectopic pregnancy: a systematic review. Fertil Steril 2007;87:481–4. Lipscomb GH, Puckett KJ, Bran D, Ling FW. Management of separation pain after single-dose methotrexate therapy for ectopic pregnancy. Obstet Gynecol 1999;93:590–3. Rozenberg 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;18:1802–8. Carson SA, Buster JE. Ectopic pregnancy. N Engl J Med 1993;329:1174–81. Tanaka T, Hayashi H, Kutsuzawa T, Fujimoto S, Ichinoe K. Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case. Fertil Steril 1982;37:851–2. Stovall TG, Ling FW. Ectopic pregnancy: diagnostic and therapeutic algorithms minimizing surgical intervention. J Reprod Med 1993;38:807–12. Barnhart K, Hummel AC, Sammel MD, Menon S, Jain J, Chakhtoura N. Use of ‘‘2- dose’’ regimen of methotrexate to treat ectopic pregnancy. Fertil Steril 2007;87:250–6. Jermy K, Thomas J, Doo A, Bourne T. The conservative management of interstitial pregnancy. BJOG 2004;111:1283–8. Fernandez H, Benifla JL, Madelenat P. Medical treatment of cornual pregnancy? Fertil Steril 1996;66:862. Lau S, Tulandi T. Conservative medical and surgical management of interstitial ectopic pregnancy. Fertil Steril 1999;72:207–15. Kirk E, Bourne T. The nonsurgical management of ectopic pregnancy. Curr Opin Obstet Gynecol 2006;18:587–93. Bourget P, Fernandez H, Quinquis-Desmaris V. Pharmacological treatment of ectopic pregnancy [article in French]. Therapie 1993;48:215–23. Timor-Tritsch IE. Hyperosmolar glucose injection for the treatment of heterotopic ovarian pregnancy. Obstet Gynecol 2012;120:1212–3. Allison JL, Aubuchon M, Leasure JD, Schust DJ. Hyperosmolar glucose injection for the treatment of heterotopic ovarian pregnancy. Obstet Gynecol 2012;120:449–52. Raughley MJ, Frishman GN. Local treatment of ectopic pregnancy. Semin Reprod Med 2007;25:99–115. Lang PF, Weiss PA, Mayer HO, Haas JG, Honigl W. Conservative treatment of ectopic pregnancy with local injection of hyperosmolar glucose solution or prostaglandin-F2 alpha: a prospective randomised study. Lancet 1990; 336:78–81. Rabischong B. Predicting success of laparoscopic salpingostomy for ectopic pregnancy. Obstet Gynecol 2010;116:701–7. Graczykowski JW, Mishell DR. Methotrexate prophylaxis for persistent ectopic pregnancy after conservative treatment by salpingostomy. Obstet Gynecol 1997;89:118–22. Banerjee 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;108:158–63. Elson 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;23:552–6. Kirk E, Van Calster B, Condous G, Papageorghiou AT, 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;90:264–72. van Mello NM, Mol F, Verhoeve HR, van Wely M, Adriaansa AH, Boss EA, 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;28:60–7. Fernandez H, Yves Vincent SC, Pauthier S, Audibert F, Frydman R. Randomized trial of conservative laparoscopic treatment and methotrexate adminis- 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. tration in ectopic pregnancy and subsequent fertility. Hum Reprod 1998;13: 3239–43. Hajenius PJ, Engelsbal S, Mol BW, Van der Veen F, Ankul WM, Bossuyt PM, et al. Randomised trial of systemic methotrexate versus laparoscopic salpingostomy in tubal pregnancy. Lancet 1997;350:774–9. Sowter MC, Farquhar CM, Petrie KJ, Gudex G. A randomised trial comparing single dose systemic methotrexate and laparoscopic surgery for the treatment of unruptured tubal pregnancy. BJOG 2001;108:192–203. Vermesh M. Conservative management of ectopic gestation. Fertil Steril 1989;51:559–67. Vermesh M, Silva PD, Rosen GF, Stein AL, Fossum GT, Sauer MV. Management of unruptured ectopic gestation by linear salpingostomy: a prospective, randomized clinical trial of laparoscopy versus laparotomy. Obstet Gynecol 1989;73:400–4. Mol F, Mol BW, Ankum WM, van der Veen F, Hajenius PJ. 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;14:309–19. Hajenius PJ, Mol F, Mol BW, Bossuyt PM, Ankum WM, van der Veen F. Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev 2007;1: CD000324. Akira S, Negishi Y, Abe T, Ichikawa M, Takeshita T. Prophylactic intratubal injection of methotrexate after linear salpingostomy for prevention of persistent ectopic pregnancy. J Obstet Gynaecol Res 2008;34:885–9. Saraj AJ, Wilcox JG, Najmabadi S, Stein SM, Johnson MB, Paulson RJ. Resolution of hormonal markers of ectopic gestation: a randomized trial comparing single-dose intramuscular methotrexate with salpingostomy. Obstet Gynecol 1998;92:989–94. Colacurci N, De Franciscis P, Zarcone R, Fortunato N, Passaro M, Mollo A, et al. Time length of negativization of hCG serum values after either surgical or medical treatment of ectopic pregnancy. Panminerva Med 1998;40:223–5. Vaissade L, Gerbaud L, Pouly JL, Job-Spira N, Bouyer J, Coste J, et al. Costeffectiveness analysis of laparoscopic surgery versus methotrexate: comparison of data recorded in an ectopic pregnancy registry [article in French]. J Gynecol Obstet Biol Reprod 2003;32:447–58. Nieuwkerk PT, Hajenius PJ, Ankum WM, Van der Veen F, Wijker W, Bossuyt PM. Systemic methotrexate therapy versus laparoscopic salpingostomy in patients with tubal pregnancy. Part I. Impact on patients' healthrelated quality of life. Fertil Steril 1998;70:511–7. van Mello NM, Mol F, Opmeer BC, de Bekker-Grob EW, Essink-Bot ML, Ankum WM, et al. Salpingotomy or salpingectomy in tubal ectopic pregnancy: what do women prefer? Reprod Biomed Online 2010;21:687–93. Allonier C, Ego A, Gerbaud L, Job-Spira N, Subtil D, Bouyer J. Comparison of fertility rates after ectopic pregnancy in Auvergne and Lille regions [article in French]. J Gynecol Obstet Biol Reprod 2003;32:439–46. Bouyer J, Fernandez H, Coste J, Pouly JL, Job-Spira N. Fertility after ectopic pregnancy: 10-year results in the Auvergne Registry [article in French]. J Gynecol Obstet Biol Reprod 2003;32:431–8. Bouyer J, Coste J, Shojael T, Pouly JL, Fernandez H, Gerbaud L, et al. Risk factors for extrauterine pregnancy in women using an intrauterine device. Fertil Steril 2000;74:899–908. Dias Pereira G, Hajenius PJ, Mol BW, Ankum WM, Hemrika DJ, Bossuyt PM, et al. Fertility outcome after systemic methotrexate and laparoscopic salpingostomy for tubal pregnancy. Lancet 1999;353:724–5. Zilber U, Pansky M, Bukovsky I, Golan A. Laparoscopic salpingostomy versus laparoscopic local methotrexate injection in the management of unruptured ectopic gestation. Am J Obstet Gynecol 1996;175:600–2. Nilsson UW, Wilmann T, Kaitu'u-Lino T, Whitehead C, Dimitriadis E, Menkhorst E, et al. Effects of Gefitinib, an epidermal growth factor receptor inhibitor on human placental cell growth. Obstet Gynecol 2013;122:737–51. Skubisz MM, Horne AW, Johns TG, Nilsson UW, Duncan WC, Wallace EM, et al. Combination gefitinib and methotrexate compared with methotrexate alone to treat ectopic pregnancy. Obstet Gynecol 2013;122:745–51. Gong W, Ren H, Han C, Li Y, Wu Z. Superselective uterine arterial embolization combined with transcatheter intra-arterial methotrexate infusion in 40 cases with fallopian tube ectopic pregnancy. Clin Exp Obstet Gynecol 2013; 40:222–6. VOL. 101 NO. 3 / MARCH 2014
© Copyright 2024