Reproductive performance after methotrexate treatment of ectopic pregnancy Thomas G. Stovall, MD: Frank W. Ling, MD,. and John E. Buster, MDb Memphis, Tennessee The purpose of this study was to examine return of reproductive potential, hysterosalpingographic findings, and time to conception in patients treated with methotrexate and citrovorum factor for unruptured ectopic pregnancy. Fifty-seven patients with unruptured ectopic pregnancies .
t.)
0.8
C
CQ
C
CI
...
G)
c.. '0
0.6
~
:.0 CQ
0.4
...0
~
c..
0.2
o
3
2
5
4
Fig. 1. Probability of pregnancy by time attempting conception with methotrexate. after treatment ,
Table I. Comparison of ectopic site with hysterosalpingographic findings Hysterosalpingogram findings Patent Ectopic site
No.
Right (n = 18) Left (n = 5)
14
TOTAL
(N
= 23)
5
19
-'
Nonpatent
I
%
No.
77.8
4
22.2
0
00.0
4
17.4
100 82.6
%
after disappearance ofhCG. In the majority of patients, normal menses returned just before completion of therapy or within the first 30 days after disappearance of hCG. In only one patient was this period longer than 45 days. Menses did not resume in this patient for 157 days at which time the patient sought treatment. The patient was morbidly obese and had withdrawal bleeding after a lO-day course of medroxyprogesterone acetate therapy. Kamrava et al. 14 showed that serum clearance of hCG may take up to at least 24 days after a conservative surgical procedure. Our mean time to disappearance of hCG is similar, although somewhat prolonged in a few patients with higher heG titers. Thus use of methotrexate does not appear to unduly delay hCG disappearance or return of menses. The probability of conception after methotrexatecitrovorum factor treatment is 25% and 87% at 1 and 4 months, respectively (Fig. 1). This is comparable to normal women with azospermic husbands who undergo artificial insemination with fresh semen. In one such series, Corson" found that 72% of pregnancies occurred by the end of the third cycle, a figure comparable to our study group (Fig. 1). However, our figures are somewhat superior to the surgical series of
Vermesh et al.,13 in which the pregnancy rate was 56% (10/18) in patients undergoing laparoscopic salpingostomy and 58% (1111 9) in those treated by laparotomy salpingostomy. All pregnancies reported in this series were conceived within 6 months of operation. Our study is reassuring because 78.6% of patients (1111 4) seeking pregnancy were able to conceive. However, our ability to draw firm conclusions is hindered by 22.8% of patients lost to follow-up after therapy completion and the small number of patients seeking pregnancy. It is also possible that the 44 patients available for follow-up and 14 patients attempting pregnancy are not representative of the entire study population. On the basis of follow-up data available on patients treated with methotrexate for gestational trophoblastic disease, there does not appear to be an increased incidence of congenital malformation in subsequent pregnancies. 16 Although our study is not large enough to eliminate this possibility in this group of patients, it would seem unlikely given the current knowledge based on experience with gestational trophoblastic disease. The intrauterine pregnancy rate of 90.1 % in this series is superior to the 49% to 70% intrauterine pregnancy rate in patients treated by linear salpingostomy reported in a recent review. 16 In addition, our recurrent ectopic rate of 9.1 % is comparable to the rate of 13% (0 to 22) reported in the same series. We speculate that the higher intrauterine pregnancy rate is not a result of methotrexate-citrovorum factor treatment alone, but a result of earlier diagnosis with an intensive screening program. By minimizing the time in which trophoblastic tissue can invade tubal mucosa, the risk of anatomic distortion with subsequent recurrent ectopic pregnancy is also lessened. We also hypothesize that medical therapy results in less tissue damage to the tube than any surgical procedure, regardless of how conservative the operation. We conclude that methotrexate-citrovorum factor treatment of unruptured ectopic pregnancy does not impair return of menses, helps restore tubal anatomy as demonstrated by the hysterosalpingography, and does not appear to impair subsequent reproductive performance. The pregnancy rates after this form of therapy appear to be better than those achieved by traditional conservative surgical methods, comparable to laparoscopic salpingostomy, and comparable to normal women with azoospermic husbands who undergo artificial insemination with fresh semen. The principal value of this safe, effective form of treatment is that it bypasses the risk, cost, and morbidity of surgical intervention. This preliminary study is reassuring evidence that the benefits of methotrexate-citrovorum factor treatment are not offset by any loss of reproductive efficacy.
Volume 162 Number 6
REFERENCES I. Schoen .lA, Nowak RJ. Repeat ectopic pregnancy: a 16-
year clinical survey. Obstet Gynecol 1975;45:542-6. 2. KitchinJD, Wein RM, Nunley we, Thiagarajah S, Thornton WN. Ectopic pregnancy: current clinical trends. AM .I OBSTET (;Y;\IECOI. 1979; 134:870-6. 3. Bronson RA. Tubal pregnancy and infertility. Ferti! Steril 1977;28:221-8. 4. Oelsner (;, Morad .I, Carp H, Mashiach S, Serr DM. Reproductive performance following conservative microsurgical management of tubal pregnancy. Br .I Obstet (;ynaecoI1987;94:1078-83. 5. O;'y SJ. Yillameua AL, Sand PK, Tamura RK. Conservative treatment of ectopic pregnancy with methotrexate. AMJ OBSTET GYNECOL 1986;154:1299-1306. 6. Sauer MY, Gorrill MJ, Rodi lA, et al. Non-surgical management of unruptured ectopic pregnancy: an extended clinical trial. Ferti! Steril 1987;48:752-5. 7. Stovall T(;, Ling FW, Buster .IE. Outpatient chemotherapy of un ruptured ectopic pregnancy. Fertil Steril 1989; 51 :435-8. 8. Yermesh M, Silva PD, Sauer MY, Yargyas .1M, Lobo RA. Persistent tubal ectopic gestation: patterns of circulating l3-human chorionic gonadotropin and progesterone, and management options. Fertil Steril 1988;50:584-8. 9. Cartwright PS, Herbert eM III, Maxson WS. Operative laparoscopy for tbe management of tubal pregnancy. .I Reprod Med 1986;31 :589-91. 10. Stovall TG, Ling FW, Smith we, Felker R, Rasco BJ, Buster .IE. Successful non-surgical treatment of cervical pregnancy with methotrexate. Ferti! Steril 1988;50: 672-4. II. Mithcell DE, McSwain HF, McCarthy .lA, Peterson HB. Hysterosalpingographic evaluation of tubal patency after ectopic pregnancy. AMJ OBSTET CYNECOL 1987; 157 :61822. 12. Stovall TG, Ling FW, Cope BJ, Buster .IE. Preventing ruptured ectopic pregnancy utilizing a single serum progesterone. AM J OBSTET GYNECOI. 1989; 160: 1425-31. 13. Yermesh M, Silva PD, Rosen GF, Stein AL, Fosum CT. Sauer MY. Management of unruptured ectopic pregnancy by linear salpingostomy: a prospective randomized clinical trial of laparoscopy versus laparotomy. Obstet Gynecol 1989;73:400-4. 14. Kamrava MM, Taymor ML, Berger MJ. Thompson IE. Seibel MM. Disappearance of human chorionic gonadotropin following removal of ectopic pregnancy. Obstet (;ynecol 1983;62:486-8. 15. Corson SL. Factors affecting donor artificial insemination success rates. Fertil Steril 1980;33:415-22. 16. Ross GT. Congenital anomalies among children born to mothers receiving chemotherapy for gestational trophoblastic neoplasms. Cancer 1976;37: 1043-7. 17. Yermesh M. Conservative management of ectopic gestation. Fertil Steril 1989;51 :559-67.
Editors' note: This manuscript was revised after these discussions were presented. Discussion DR. BRYAN D. COWAN, Jackson, Mississippi. To my knowledge, the first report of successful treatment of all ectopic pregnancy with methotrexate occurred in 1982.' After this report, a few case reports depicted anecdotal experience of unusual presentations of ectopic pregnancies including cervical pregnancy,2 cornual pregnancy," and persistent trophoblast 4 after conservative surgical management of unruptured tubal pregnancies. In 1985 the first clinical study of metho-
Ectopic pregnancy and methotrexate
1623
trexate as primary treatment for ectopic pregnancy was reported at the fifty-third annual meeting of this association in New Orleans.' Dr. Steve Ory and his colleagues described six patients with confirmed unruptured tubal pregnancies that were treated primarily with methotrexate. Since then several institutions have reported their experience in treating tubal pregnancies with methotrexate. This report addresses an important question that all of us who have treated or have considered treating patients with tubal gestations with methotrexate have asked: "Do patients who undergo this treatment have preservation of tubal and reproductive function?" I am impressed with the authors' results. Some aspects of this study, however, make the ultimate interpretation of this data difficult. For example, we do not know the status of the unaffected tube in the 14 patients who were attempting pregnancy. It is entirely possible that the unaffected tube was perfectly normal and therefore posed no risk for repeat ectopic pregnancy on the contralateral side or impairment of fertility. If the 10 patients who conceived an intrauterine gestation were disproportionately composed of women with normal contralateral anatomy, a distinct reproductive advantage would be granted to this group. On the other hand, women with contralateral tubal disease would be at risk for repeat ectopic pregnancy, and reduced fertility. An additional shortcoming is the failure to specify an ampullary or isthmic location for the ectopic pregnancy. The data cannot be analzyed to determine if patients with ampullary or isthmic tubal pregnancies have the same clinical outcome and subsequent reproductive potential after treatment with methotrexate. The trophoblast may invade the muscularis more aggressively in isthmic ectopic pregnancies," and the subsequent outcome ofthese patients may be different than ampullary gestations. I agree with the authors that this form of therapy, on the basis of their data, does not appear to impair subsequent reproductive performance. However, before we embrace this information completely, subsequent studies by other authors and other institutions should confirm these observations. The claim that this therapy reduces the risk, cost, and morbidity of surgical intervention for ectopic pregnancy cannot be supported. All patients in this study underwent laparoscopy to confirm the diagnosis. It is exceptionally difficult for most gynecologists to recognize an ectopic pregnancy at the time of laparoscopy and allow this pathologic condition to be untreated by operation. Most gynecologists would remove the ectopic pregnancy and forego the cost of medical treatment. However, I can foresee when it may become practical to treat ectopic pregnancies without operation. Visualization by either ultrasonography or laparoscopy is currently required to confirm the diagnosis of an ectopic gestation. When an ectopic gestation can be defined without the need for operation, methotrexate therapy may be the treatment of choice. Ultrasonographically guided direct injection of methotrexate into
1624 Stovall, Ling, and Buster
the gestational sac has successfully cured women in whom the ectopic gestation could be visualized. 7 Once diagnostic operation can be avoided, the true potential for this therapy as the primary treatment for tubal pregnancies will be realized. We are greatly encouraged by the favorable reproductive outcome reported here. I have two questions for the authors. First, have they considered intraoperative injection of any ectopic gestations with methotrexate? Second, are they aware of the condition of the contralateral tube in the 10 of 14 women with an intrauterine gestation, and three who have failed to conceive, and one with a repeat ectopic pregnancy? REFERENCES 1. Tanaka T, Hayashi H, Kutsuzawa T, Fujimoto S, Ichinoe
K· Trf;',mnlim 1)1' imlirnidal !il:~Qpk pr!ignanl:y whh m!i~h= 1982; 3Nl51-2.
\!I1t·Kille: IT)lOII 0(' II slIuTss{'1I1 niSI:. Ferri! Slni!
WS, Fulton JW, Fletcher V Jr, Velat CA, White JT. Cervical pregnancy treated with methotrexate. NC Med J 1983;44:91-3. Brandes MC, Youngs DD, Goldstein DP, Parmby TH. Treatment of cornual pregnancy with methotrexate: case report. AM J OBSTET GYNECOL 1986; 155:655-7. Cowan RD, McGehee RP, Bates GW. Treatment of persistent ectopic pregnancy with methotrexate and leukovorum rescue: a case report. Obstet Gynecol 1986;67:50S-5IS. Ory SJ, Villanueva AL, Sand PK, Tamura RK. Conservative treatment of ectopic pregnancy with methotrexate. AM J OBSTET GVNECOL 1986; 154: 1299-306. Pauerstein CJ, Croxatto HB, Eddy CA, Ramzy I, Walters MD. Anatomy and pathology of tubal pregnancy. Obstet Gynecol 1986;67:301-8. Feichtinger W, Kemeter P. Conservative treatment of ectopic pregnancy by transvaginal aspiration under sonographic control and methotrexate injection. Lancet 1987; 1:381-2.
2. Farabow
3. 4. 5. 6. 7.
DR. M. WAYNE HEINE, Tucson, Arizona. The authors have provided additional information on return of reproductive function in patients treated medically for ectopic pregnancy. They studied return of menses, pregnancy rate, and pregnancy outcome. Menses returned within 26 days, and 82% of the affected tubes were patent after therapy. The pregnancy rate was 87% within 4 months, similar to donor insemination programs. The intrauterine pregnancy rate was 90%. This was compared with surgical treatment with a pregnancy rate of 57%, and the intrauterine pregnancy rate varies between 40% and 70%. The recurrent ectopic rate is similar in the two groups. Because of the restrictive criteria for a patient to enter the study, (i.e., tubal pregnancy of less than 3 cm in diameter), only 44 patients were available for follow-up of 2 to 15 months. Only 14 patients desired pregnancy. Because of this small number of patients (one patient in either direction), tubal pregnancy or abortion would alter the percentages greatly. The results are not comparable to the surgical method oftreatment because the study patients had very early tubal pregnancies (less than 3 cm). The
June 1990 Am J Obstet Gynecol
surgical series reported included more advanced tubal pregnancies. With more advanced tubal pregnancies there is more bleeding, distortion of the tubes, and invasion by the trophoblast. The method described by the authors is less costly and would save approximately $1200 per patient in our institution. There also should be less dissemination of trophoblastic materials with medical therapy. The study would have been more informative if there had been an increased number of patients, and had alternated between medical and surgical therapy using the restrictive criteria. The comparison of reproductive function, morbidity, and cost would have been more meaningful. DR. JOHN L. AUSTIN, Memphis, Tennessee. Dr. Stovall, what would be the appropriateness of a direct in.i"dillll IIf lfltlthoi.rt;Kail;, pm'hap~ dllrin~ va~in,11 prnh(' ullrasollography, ill terms ot omh {'(I'll cfte{'(ivcnc'l'l and technical ability? Are you going (0 study this in the future? DR. DANIEL A. RIGHTMIRE, Springfield, Illinois. Are the results so impressive thal they preclude a prospective randomized trial? DR. STOVALL (Closing). To update you on our progress, we have treated >80 unruptured ectopic pregnancies with methotrexate. Of these, 95% were successfully treated without further intervention. Of the three failures, two can be related to the presence of cardiac activity in advanced gestations with high hCG levels; the third rupture remains unexplained. Current contraindications to methotrexate therapy include a size of :::::3 cm, rupture of the ectopic pregnancy, or the presence of cardiac activity. A study was recently reported in abstract form from Argentina in which the investigators treated ruptured ectopic pregnancies with methotrexate. In the future, these contraindications outlined may become relative contraindications. Our group has treated approximately four patients with cardiac activity with low hCG levels, all of which have had successful outcomes. To date, 16 pregnancies have occurred after methotrexate treatment; two of these were ectopics; and of some note, both were in the contralateral tube. Fourteen were intrauterine pregnancies. Thirteen of the fourteen intrauterine pregnancies are viable, and one ended with a spontaneous abortion. The role of oral methotrexate in the treatment of this condition, the role of direct injection at the time of laparoscopy or at the time of vaginal ultrasonography (operative ultrasonography) remains uncertain. There are reports of oral methotrexate use, and there are reports with direct injection of methotrexate, potassium chloride, and prostaglandin. We have attempted direct injection with transvaginal ultrasonographic guidance on two patients. Both treatments failed.
t.)
0.8
C
CQ
C
CI
...
G)
c.. '0
0.6
~
:.0 CQ
0.4
...0
~
c..
0.2
o
3
2
5
4
Fig. 1. Probability of pregnancy by time attempting conception with methotrexate. after treatment ,
Table I. Comparison of ectopic site with hysterosalpingographic findings Hysterosalpingogram findings Patent Ectopic site
No.
Right (n = 18) Left (n = 5)
14
TOTAL
(N
= 23)
5
19
-'
Nonpatent
I
%
No.
77.8
4
22.2
0
00.0
4
17.4
100 82.6
%
after disappearance ofhCG. In the majority of patients, normal menses returned just before completion of therapy or within the first 30 days after disappearance of hCG. In only one patient was this period longer than 45 days. Menses did not resume in this patient for 157 days at which time the patient sought treatment. The patient was morbidly obese and had withdrawal bleeding after a lO-day course of medroxyprogesterone acetate therapy. Kamrava et al. 14 showed that serum clearance of hCG may take up to at least 24 days after a conservative surgical procedure. Our mean time to disappearance of hCG is similar, although somewhat prolonged in a few patients with higher heG titers. Thus use of methotrexate does not appear to unduly delay hCG disappearance or return of menses. The probability of conception after methotrexatecitrovorum factor treatment is 25% and 87% at 1 and 4 months, respectively (Fig. 1). This is comparable to normal women with azospermic husbands who undergo artificial insemination with fresh semen. In one such series, Corson" found that 72% of pregnancies occurred by the end of the third cycle, a figure comparable to our study group (Fig. 1). However, our figures are somewhat superior to the surgical series of
Vermesh et al.,13 in which the pregnancy rate was 56% (10/18) in patients undergoing laparoscopic salpingostomy and 58% (1111 9) in those treated by laparotomy salpingostomy. All pregnancies reported in this series were conceived within 6 months of operation. Our study is reassuring because 78.6% of patients (1111 4) seeking pregnancy were able to conceive. However, our ability to draw firm conclusions is hindered by 22.8% of patients lost to follow-up after therapy completion and the small number of patients seeking pregnancy. It is also possible that the 44 patients available for follow-up and 14 patients attempting pregnancy are not representative of the entire study population. On the basis of follow-up data available on patients treated with methotrexate for gestational trophoblastic disease, there does not appear to be an increased incidence of congenital malformation in subsequent pregnancies. 16 Although our study is not large enough to eliminate this possibility in this group of patients, it would seem unlikely given the current knowledge based on experience with gestational trophoblastic disease. The intrauterine pregnancy rate of 90.1 % in this series is superior to the 49% to 70% intrauterine pregnancy rate in patients treated by linear salpingostomy reported in a recent review. 16 In addition, our recurrent ectopic rate of 9.1 % is comparable to the rate of 13% (0 to 22) reported in the same series. We speculate that the higher intrauterine pregnancy rate is not a result of methotrexate-citrovorum factor treatment alone, but a result of earlier diagnosis with an intensive screening program. By minimizing the time in which trophoblastic tissue can invade tubal mucosa, the risk of anatomic distortion with subsequent recurrent ectopic pregnancy is also lessened. We also hypothesize that medical therapy results in less tissue damage to the tube than any surgical procedure, regardless of how conservative the operation. We conclude that methotrexate-citrovorum factor treatment of unruptured ectopic pregnancy does not impair return of menses, helps restore tubal anatomy as demonstrated by the hysterosalpingography, and does not appear to impair subsequent reproductive performance. The pregnancy rates after this form of therapy appear to be better than those achieved by traditional conservative surgical methods, comparable to laparoscopic salpingostomy, and comparable to normal women with azoospermic husbands who undergo artificial insemination with fresh semen. The principal value of this safe, effective form of treatment is that it bypasses the risk, cost, and morbidity of surgical intervention. This preliminary study is reassuring evidence that the benefits of methotrexate-citrovorum factor treatment are not offset by any loss of reproductive efficacy.
Volume 162 Number 6
REFERENCES I. Schoen .lA, Nowak RJ. Repeat ectopic pregnancy: a 16-
year clinical survey. Obstet Gynecol 1975;45:542-6. 2. KitchinJD, Wein RM, Nunley we, Thiagarajah S, Thornton WN. Ectopic pregnancy: current clinical trends. AM .I OBSTET (;Y;\IECOI. 1979; 134:870-6. 3. Bronson RA. Tubal pregnancy and infertility. Ferti! Steril 1977;28:221-8. 4. Oelsner (;, Morad .I, Carp H, Mashiach S, Serr DM. Reproductive performance following conservative microsurgical management of tubal pregnancy. Br .I Obstet (;ynaecoI1987;94:1078-83. 5. O;'y SJ. Yillameua AL, Sand PK, Tamura RK. Conservative treatment of ectopic pregnancy with methotrexate. AMJ OBSTET GYNECOL 1986;154:1299-1306. 6. Sauer MY, Gorrill MJ, Rodi lA, et al. Non-surgical management of unruptured ectopic pregnancy: an extended clinical trial. Ferti! Steril 1987;48:752-5. 7. Stovall T(;, Ling FW, Buster .IE. Outpatient chemotherapy of un ruptured ectopic pregnancy. Fertil Steril 1989; 51 :435-8. 8. Yermesh M, Silva PD, Sauer MY, Yargyas .1M, Lobo RA. Persistent tubal ectopic gestation: patterns of circulating l3-human chorionic gonadotropin and progesterone, and management options. Fertil Steril 1988;50:584-8. 9. Cartwright PS, Herbert eM III, Maxson WS. Operative laparoscopy for tbe management of tubal pregnancy. .I Reprod Med 1986;31 :589-91. 10. Stovall TG, Ling FW, Smith we, Felker R, Rasco BJ, Buster .IE. Successful non-surgical treatment of cervical pregnancy with methotrexate. Ferti! Steril 1988;50: 672-4. II. Mithcell DE, McSwain HF, McCarthy .lA, Peterson HB. Hysterosalpingographic evaluation of tubal patency after ectopic pregnancy. AMJ OBSTET CYNECOL 1987; 157 :61822. 12. Stovall TG, Ling FW, Cope BJ, Buster .IE. Preventing ruptured ectopic pregnancy utilizing a single serum progesterone. AM J OBSTET GYNECOI. 1989; 160: 1425-31. 13. Yermesh M, Silva PD, Rosen GF, Stein AL, Fosum CT. Sauer MY. Management of unruptured ectopic pregnancy by linear salpingostomy: a prospective randomized clinical trial of laparoscopy versus laparotomy. Obstet Gynecol 1989;73:400-4. 14. Kamrava MM, Taymor ML, Berger MJ. Thompson IE. Seibel MM. Disappearance of human chorionic gonadotropin following removal of ectopic pregnancy. Obstet (;ynecol 1983;62:486-8. 15. Corson SL. Factors affecting donor artificial insemination success rates. Fertil Steril 1980;33:415-22. 16. Ross GT. Congenital anomalies among children born to mothers receiving chemotherapy for gestational trophoblastic neoplasms. Cancer 1976;37: 1043-7. 17. Yermesh M. Conservative management of ectopic gestation. Fertil Steril 1989;51 :559-67.
Editors' note: This manuscript was revised after these discussions were presented. Discussion DR. BRYAN D. COWAN, Jackson, Mississippi. To my knowledge, the first report of successful treatment of all ectopic pregnancy with methotrexate occurred in 1982.' After this report, a few case reports depicted anecdotal experience of unusual presentations of ectopic pregnancies including cervical pregnancy,2 cornual pregnancy," and persistent trophoblast 4 after conservative surgical management of unruptured tubal pregnancies. In 1985 the first clinical study of metho-
Ectopic pregnancy and methotrexate
1623
trexate as primary treatment for ectopic pregnancy was reported at the fifty-third annual meeting of this association in New Orleans.' Dr. Steve Ory and his colleagues described six patients with confirmed unruptured tubal pregnancies that were treated primarily with methotrexate. Since then several institutions have reported their experience in treating tubal pregnancies with methotrexate. This report addresses an important question that all of us who have treated or have considered treating patients with tubal gestations with methotrexate have asked: "Do patients who undergo this treatment have preservation of tubal and reproductive function?" I am impressed with the authors' results. Some aspects of this study, however, make the ultimate interpretation of this data difficult. For example, we do not know the status of the unaffected tube in the 14 patients who were attempting pregnancy. It is entirely possible that the unaffected tube was perfectly normal and therefore posed no risk for repeat ectopic pregnancy on the contralateral side or impairment of fertility. If the 10 patients who conceived an intrauterine gestation were disproportionately composed of women with normal contralateral anatomy, a distinct reproductive advantage would be granted to this group. On the other hand, women with contralateral tubal disease would be at risk for repeat ectopic pregnancy, and reduced fertility. An additional shortcoming is the failure to specify an ampullary or isthmic location for the ectopic pregnancy. The data cannot be analzyed to determine if patients with ampullary or isthmic tubal pregnancies have the same clinical outcome and subsequent reproductive potential after treatment with methotrexate. The trophoblast may invade the muscularis more aggressively in isthmic ectopic pregnancies," and the subsequent outcome ofthese patients may be different than ampullary gestations. I agree with the authors that this form of therapy, on the basis of their data, does not appear to impair subsequent reproductive performance. However, before we embrace this information completely, subsequent studies by other authors and other institutions should confirm these observations. The claim that this therapy reduces the risk, cost, and morbidity of surgical intervention for ectopic pregnancy cannot be supported. All patients in this study underwent laparoscopy to confirm the diagnosis. It is exceptionally difficult for most gynecologists to recognize an ectopic pregnancy at the time of laparoscopy and allow this pathologic condition to be untreated by operation. Most gynecologists would remove the ectopic pregnancy and forego the cost of medical treatment. However, I can foresee when it may become practical to treat ectopic pregnancies without operation. Visualization by either ultrasonography or laparoscopy is currently required to confirm the diagnosis of an ectopic gestation. When an ectopic gestation can be defined without the need for operation, methotrexate therapy may be the treatment of choice. Ultrasonographically guided direct injection of methotrexate into
1624 Stovall, Ling, and Buster
the gestational sac has successfully cured women in whom the ectopic gestation could be visualized. 7 Once diagnostic operation can be avoided, the true potential for this therapy as the primary treatment for tubal pregnancies will be realized. We are greatly encouraged by the favorable reproductive outcome reported here. I have two questions for the authors. First, have they considered intraoperative injection of any ectopic gestations with methotrexate? Second, are they aware of the condition of the contralateral tube in the 10 of 14 women with an intrauterine gestation, and three who have failed to conceive, and one with a repeat ectopic pregnancy? REFERENCES 1. Tanaka T, Hayashi H, Kutsuzawa T, Fujimoto S, Ichinoe
K· Trf;',mnlim 1)1' imlirnidal !il:~Qpk pr!ignanl:y whh m!i~h= 1982; 3Nl51-2.
\!I1t·Kille: IT)lOII 0(' II slIuTss{'1I1 niSI:. Ferri! Slni!
WS, Fulton JW, Fletcher V Jr, Velat CA, White JT. Cervical pregnancy treated with methotrexate. NC Med J 1983;44:91-3. Brandes MC, Youngs DD, Goldstein DP, Parmby TH. Treatment of cornual pregnancy with methotrexate: case report. AM J OBSTET GYNECOL 1986; 155:655-7. Cowan RD, McGehee RP, Bates GW. Treatment of persistent ectopic pregnancy with methotrexate and leukovorum rescue: a case report. Obstet Gynecol 1986;67:50S-5IS. Ory SJ, Villanueva AL, Sand PK, Tamura RK. Conservative treatment of ectopic pregnancy with methotrexate. AM J OBSTET GVNECOL 1986; 154: 1299-306. Pauerstein CJ, Croxatto HB, Eddy CA, Ramzy I, Walters MD. Anatomy and pathology of tubal pregnancy. Obstet Gynecol 1986;67:301-8. Feichtinger W, Kemeter P. Conservative treatment of ectopic pregnancy by transvaginal aspiration under sonographic control and methotrexate injection. Lancet 1987; 1:381-2.
2. Farabow
3. 4. 5. 6. 7.
DR. M. WAYNE HEINE, Tucson, Arizona. The authors have provided additional information on return of reproductive function in patients treated medically for ectopic pregnancy. They studied return of menses, pregnancy rate, and pregnancy outcome. Menses returned within 26 days, and 82% of the affected tubes were patent after therapy. The pregnancy rate was 87% within 4 months, similar to donor insemination programs. The intrauterine pregnancy rate was 90%. This was compared with surgical treatment with a pregnancy rate of 57%, and the intrauterine pregnancy rate varies between 40% and 70%. The recurrent ectopic rate is similar in the two groups. Because of the restrictive criteria for a patient to enter the study, (i.e., tubal pregnancy of less than 3 cm in diameter), only 44 patients were available for follow-up of 2 to 15 months. Only 14 patients desired pregnancy. Because of this small number of patients (one patient in either direction), tubal pregnancy or abortion would alter the percentages greatly. The results are not comparable to the surgical method oftreatment because the study patients had very early tubal pregnancies (less than 3 cm). The
June 1990 Am J Obstet Gynecol
surgical series reported included more advanced tubal pregnancies. With more advanced tubal pregnancies there is more bleeding, distortion of the tubes, and invasion by the trophoblast. The method described by the authors is less costly and would save approximately $1200 per patient in our institution. There also should be less dissemination of trophoblastic materials with medical therapy. The study would have been more informative if there had been an increased number of patients, and had alternated between medical and surgical therapy using the restrictive criteria. The comparison of reproductive function, morbidity, and cost would have been more meaningful. DR. JOHN L. AUSTIN, Memphis, Tennessee. Dr. Stovall, what would be the appropriateness of a direct in.i"dillll IIf lfltlthoi.rt;Kail;, pm'hap~ dllrin~ va~in,11 prnh(' ullrasollography, ill terms ot omh {'(I'll cfte{'(ivcnc'l'l and technical ability? Are you going (0 study this in the future? DR. DANIEL A. RIGHTMIRE, Springfield, Illinois. Are the results so impressive thal they preclude a prospective randomized trial? DR. STOVALL (Closing). To update you on our progress, we have treated >80 unruptured ectopic pregnancies with methotrexate. Of these, 95% were successfully treated without further intervention. Of the three failures, two can be related to the presence of cardiac activity in advanced gestations with high hCG levels; the third rupture remains unexplained. Current contraindications to methotrexate therapy include a size of :::::3 cm, rupture of the ectopic pregnancy, or the presence of cardiac activity. A study was recently reported in abstract form from Argentina in which the investigators treated ruptured ectopic pregnancies with methotrexate. In the future, these contraindications outlined may become relative contraindications. Our group has treated approximately four patients with cardiac activity with low hCG levels, all of which have had successful outcomes. To date, 16 pregnancies have occurred after methotrexate treatment; two of these were ectopics; and of some note, both were in the contralateral tube. Fourteen were intrauterine pregnancies. Thirteen of the fourteen intrauterine pregnancies are viable, and one ended with a spontaneous abortion. The role of oral methotrexate in the treatment of this condition, the role of direct injection at the time of laparoscopy or at the time of vaginal ultrasonography (operative ultrasonography) remains uncertain. There are reports of oral methotrexate use, and there are reports with direct injection of methotrexate, potassium chloride, and prostaglandin. We have attempted direct injection with transvaginal ultrasonographic guidance on two patients. Both treatments failed.
