- Email: [email protected]
Laparoscopy, in vitro fertilization, and endometriosis: an enigma
Laparoscopy, in vitro fertilization, and endometriosis: an enigma G. David Adamson, M.D., F.R.C.S.C., F.A.C.O.G., F.A.C.S. Fertility Physicians of Northern California, Palo Alto, California
Studies on the respective roles of laparoscopic surgery and IVF in infertile patients with endometriosis and endometriomas are difficult to perform. Appropriate patient management is complex and requires a sophisticated understanding of individualized evidence-based decision making, surgical judgment and technical skills for laparoscopy, and thoughtful utilization of IVF technologies. (Fertil Steril威 2005;84:1582– 4. ©2005 by American Society for Reproductive Medicine.)
Endometriosis is an enigmatic condition with an array of treatment options that can create difficult decisions among even experienced clinicians. The paper by Littman et al. (1) concludes that laparoscopic endometriosis treatment can be effective following failed IVF and raises important, complex issues about the respective roles of operative laparoscopy and IVF. However, the study’s limitations, some of which have been addressed by the authors, must be considered in evaluating their conclusion. This study’s power is limited because it is small (subject n ⫽ 29) and, because it is retrospective, it cannot give a detailed description of the population of patients and the dynamics of their treatment. This includes the conditions under which IVF was initially chosen as the most appropriate treatment. Some unknown factors, especially for subgroups, include patient age, whether the first laparoscopy was for diagnosis or treatment, bias in the self-selected control group of those patients choosing not to have laparoscopic treatment, and bias in treatment decisions in the subject group. Some patients had only 1 IVF cycle before entering the study. Because IVF is successful less than half the time even in ideal patients, it is not known on what basis decisions were made to consider alternative treatments after only 1 or 2 IVF cycles, especially because there is only a slight reduction in success rates with IVF with increasing numbers of cycles (2). Patient selection criteria for the 8 patients who underwent IVF following laparoscopic treatment are also not described. Factors that were considered in deciding to return to IVF treatment are unknown. Twelve patients conceived spontaneously and 2 with clomiphene and intrauterine insemination. It is not known if these patients’ characteristics, such as age, stage, and duration of infertility, were similar to those of the other patients. Analysis of pregnancy rates would have been more robust with life table analysis. Approximately half (14/29) conceived after laparoscopic surgery without further IVF, a Received May 2, 2005; revised and accepted May 2, 2005. Reprint requests: G. David Adamson, Fertility Physicians of Northern California, 540 University Avenue, Suite 200, Palo Alto, California 94301 (FAX: 650-322-1730; E-mail: [email protected]).
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proportion within the expected range following laparoscopic treatment (3). In the nonlaparoscopy control group 13/35 conceived: 2 spontaneously and 11 from repeat IVF. This proportion (13/35) is not statistically different than those who conceived after surgery but before IVF (14/29). It would be interesting to know whether it took 11 or more IVF cycles for the 11 conceptions. Not surprisingly, older patients and those with stage 4 disease did not conceive as often, consistent with the literature (3, 4). Extensive endometriosis (American Society for Reproductive Medicine score ⬎71) is associated with reduced pregnancy rates (5). Such disease basically requires at least two of the three following presentations of endometriosis: endometriomas, complete cul de sac obliteration, and extensive dense adhesions. However, it is not clear whether pregnancy rates otherwise decrease with increasing stage of disease, some studies demonstrating a reduction and others not (3, 6, 7). Furthermore, although it is probably self-evident that IVF is of value in advanced disease owing to the very low background pregnancy rate and the tangible rate of success with the procedure, the value of IVF in early-stage disease is as yet unproven. In other words, whereas pregnancies certainly occur quite rapidly with IVF in women with endometriosis or any other diagnosis, it is unclear whether 1 cycle of IVF is comparable to 1 month, 6 months, 2 years, or longer of attempting conception naturally (8). Given the not-different proportions conceiving in the laparoscopy and nonlaparoscopy groups (and therefore similar benefit), the elemental question becomes, “Which treatment has the greatest cost in terms of dollars, time, health risk, and emotional burden?” Undoubtedly this question has different answers for different patients. The impact of the diagnosis of endometriosis on outcomes with IVF treatment is not yet clear. There are no large randomized clinical trials to answer several open issues, and cohort trials have been inconclusive (9). The issue of the value of laparoscopic treatment of endometriosis prior to IVF is admittedly complex and has been addressed by the authors, but their conclusions are not universally shared.
Fertility and Sterility姞 Vol. 84, No. 6, December 2005 Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/05/$30.00 doi:10.1016/j.fertnstert.2005.05.071
This controversy is especially true when endometriomas are present, since there are no randomized trials and cohort data are conflicting (7, 10, 11). It is true that laparoscopy and pathologic diagnosis are necessary to confirm endometriomas, and that treatment must be tailored to the type of endometrioma, with some controversy still existing as to the best approach (12). Fertilization rates may or may not decrease with stage 3 and 4 endometriosis. In the Littman et al. (1) study, 13/19 patients with stage 3 or 4 disease conceived following operative laparoscopy, a very substantial proportion. The literature is not conclusive on this issue (6, 7, 13, 14). So it is not clear whether or not the 8 patients who conceived through IVF following laparoscopic surgery actually benefited from the surgery. It is hoped that the current research in metabolic markers for endometriosis and implantation will lead to better understanding, treatment, and outcomes in the future, but it cannot yet be demonstrated convincingly that surgery improves implantation rates with or without IVF or that it improves pregnancy rates for subsequent IVF cycles. Though the authors believe that the subset of patients who have failed multiple cycles of IVF may harbor a certain type of endometriosis which allows them to benefit from thorough surgical therapy, current data cannot substantiate this conclusion. They acknowledge that the best way to answer these questions is with a prospective randomized controlled trial, admittedly very difficult with surgical questions. Despite these problems with study size and design, which limit the ability to generalize its conclusions, and the impossibility of gaining unanimity based on good evidence regarding the role of surgery relative to IVF, the paper importantly emphasizes the under-utilized role of laparoscopic surgery in management of infertile patients. Indeed, it is generally agreed that laparoscopic surgery can improve pregnancy rates not only for minimal and mild disease, but also for more advanced disease (3, 15). There are several reasons why laparoscopic surgery is less commonly employed today than it has been in the past: higher success rates with IVF, fewer highly skilled laparoscopic surgeons, and relatively poor managed-care insurance reimbursement for laparoscopic surgery. Operative laparoscopy’s role before or after IVF is more complex. There are no sufficiently powered prospective randomized trials evaluating the effect on pregnancy outcome of surgical treatment followed by IVF versus IVF alone. (4, 14) Two small retrospective studies comparing the pregnancy rate after IVF to reoperation showed pregnancy rates 9 –12 months following surgery of 21%–24% (16). Therefore, IVF would seem to be a preferable alternative to repeat surgery for most patients (4). Nevertheless, there may be reason to treat large endometriomas (⬎3 cm), especially if response to ovarian stimulation drugs is poor before surgery (12). However, such surgery can be very difficult and requires a talented surgeon in order to avoid vascular and ovarian injury that might Fertility and Sterility姞
result in even poorer ovarian response postoperatively. The decision to operate is not easy. There may be a benefit of operative laparoscopic surgery for other morphologic presentations of endometriosis prior to IVF, but this has not yet been proven. The optimal approach to managing the infertile endometriosis patient is to perform a comprehensive evaluation, and then develop a treatment plan that progresses from simpler, yet effective and safe, treatments to more complex and costly treatments. The major advantage of laparoscopy performed early on is that it is as effective as 1 or 2 cycles of IVF, does not increase the risk of multiple birth, may help achieve more than 1 pregnancy, and is effective for alleviating pain and removing endometriomas. Its major disadvantages are its cost, the fact that endometriosis might not be found at laparoscopy, the need to take up to 9 –12 months postoperatively to give the operation a reasonable chance to be successful, the relative paucity of skilled surgeons, and surgical risks. The major advantage of IVF is the fact that it treats multiple infertility problems of both the female and male, has a high rate of success on just 1 attempt relative to surgery, and takes only 2–3 months to complete treatment, making it more attractive for older patients. Its major disadvantages are its cost, that it is often not covered by insurance, and the risk of multiple pregnancy. These relative benefits and costs need to be understood and explained to patients before the comprehensive treatment plan is developed. The number needed to treat to obtain 1 additional pregnancy for women undergoing laparoscopy should be estimated and discussed with each patient. Following operative laparoscopy, a realistic estimate of the chances of success needs to be made and discussed with the patient (5). The fact that IVF does not work on every patient the first time, and a life table estimate of success rates for 1, 2, and 3 cycles of IVF, also needs to be discussed with each patient. After informed consent, an individualized treatment plan can be developed, executed and modified as necessary based on patient age, duration of infertility, previous pregnancies, changing clinical conditions, and outcomes of treatment. Such an approach will usually avoid a situation in which IVF is discontinued to undergo an operative laparoscopy. However, in some situations such an approach might well be appropriate and, when indicated, the paper by Littman et al. (1) strongly suggests that a good chance of pregnancy exists when the surgery is properly performed. REFERENCES 1. Littman E, Giudice L, Lathi R, Berkler B, Milki A, Nezhat C. Role of laparoscopic treatment of endometriosis in patients with failed in vitro fertilization cycles. Fertil Steril 2005;84:1574 – 8. 2. Meldrum DR, Silverberg KM, Bustillo M, Stokes L. Success rate with repeated cycles of in vitro fertilization– embryo transfer. Fertil Steril 1998;69:1005–9. 3. Adamson GD, Pasta DJ. Surgical treatment of endometriosis-associated infertility: meta-analysis compared with survival analysis. Am J Obstet Gynecol 1994;171:1488 –505.
1583
4. The Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility. Fertil Steril 2004;81:1441– 6. 5. Adamson GD, Pasta DJ. Pregnancy rates can be predicted by validated endometriosis fertility index (EFI). Fertil Steril 2002;77(Suppl 1):S48. 6. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril 2002;77:1148 –55. 7. Spandorfer SD, Rosenwaks Z. Endometriosis. Is IVF the answer for infertility? Stage-related success rates in 1417 consecutive IVF-ET. Available at: http://www.Kenes.com/controversies/cogi3/abstracts/ 9041.doc; accessed: Nov. 1, 2005. 8. Soliman S, Daya S, Collins J, Jarrell J. A randomized trial of in vitro fertilization versus conventional treatment for infertility. Fertil Steril 1993;59:1239 – 44. 9. Dokras SA, Olive DL. Endometriosis and assisted reproductive technologies. Clin Obstet Gynecol 1999;42:687–98. 10. Garcia-Velasco JA, Mahutte NG, Corona J, Zuniga V, Giles J, Arici A, Pellicer A. Removal of endometriomas before in vitro fertilization does not improve fertility outcomes: a matched, case-control study. Fertil Steril 2004;81:1194 –7. 11. Wong BC, Gillman NC, Oehninger S, Gibbons WE, Stadtmauer LA.
1584
Adamson
Laparoscopy, IVF, endometriosis: enigma
12.
13.
14.
15.
16.
Results of in vitro fertilization in patients with endometriomas: is surgical removal beneficial? Am J Obstet Gynecol 2004;191:597– 606; discussion 606 –7. Canis M, Pouly JL, Tamburro S, Mage G, Wattiez A, Bruhat MA. Ovarian response during IVF-embryo transfer cycles after laparoscopic ovarian cystectomy for endometriotic cysts of ⬎3 cm in diameter. Hum Reprod 2001;16:2583– 6. Guzick DS, Silliman NP, Adamson GD, Buttram VC, Canis M, Malinak LR, Schenken RS. Prediction of pregnancy in infertile women based on the American Society for Reproductive Medicine’s revised classification of endometriosis. Fertil Steril 1997;67:822–9. Aboulghar MA, Mansour RT, Serour GI, Al-Inany HG, Aboulghar MM. The outcome of in vitro fertilization in advanced endometriosis with previous surgery: a case-controlled study. Am J Obstet Gynecol 2003;188:371–5. Jacobson TZ, Barlow DH, Koninckx PR, Olive D, Farquhar C. Laparoscopic surgery for subfertility associated with endometriosis. Cochrane Database Syst Rev 2002;:CD001398. Cheewadhanaraks S. Comparison of fecundity after second laparotomy for endometriosis to in vitro fertilization and embryo transfer. J Med Assoc Thai 2004;87:361– 6.
Vol. 84, No. 6, December 2005
Studies on the respective roles of laparoscopic surgery and IVF in infertile patients with endometriosis and endometriomas are difficult to perform. Appropriate patient management is complex and requires a sophisticated understanding of individualized evidence-based decision making, surgical judgment and technical skills for laparoscopy, and thoughtful utilization of IVF technologies. (Fertil Steril威 2005;84:1582– 4. ©2005 by American Society for Reproductive Medicine.)
Endometriosis is an enigmatic condition with an array of treatment options that can create difficult decisions among even experienced clinicians. The paper by Littman et al. (1) concludes that laparoscopic endometriosis treatment can be effective following failed IVF and raises important, complex issues about the respective roles of operative laparoscopy and IVF. However, the study’s limitations, some of which have been addressed by the authors, must be considered in evaluating their conclusion. This study’s power is limited because it is small (subject n ⫽ 29) and, because it is retrospective, it cannot give a detailed description of the population of patients and the dynamics of their treatment. This includes the conditions under which IVF was initially chosen as the most appropriate treatment. Some unknown factors, especially for subgroups, include patient age, whether the first laparoscopy was for diagnosis or treatment, bias in the self-selected control group of those patients choosing not to have laparoscopic treatment, and bias in treatment decisions in the subject group. Some patients had only 1 IVF cycle before entering the study. Because IVF is successful less than half the time even in ideal patients, it is not known on what basis decisions were made to consider alternative treatments after only 1 or 2 IVF cycles, especially because there is only a slight reduction in success rates with IVF with increasing numbers of cycles (2). Patient selection criteria for the 8 patients who underwent IVF following laparoscopic treatment are also not described. Factors that were considered in deciding to return to IVF treatment are unknown. Twelve patients conceived spontaneously and 2 with clomiphene and intrauterine insemination. It is not known if these patients’ characteristics, such as age, stage, and duration of infertility, were similar to those of the other patients. Analysis of pregnancy rates would have been more robust with life table analysis. Approximately half (14/29) conceived after laparoscopic surgery without further IVF, a Received May 2, 2005; revised and accepted May 2, 2005. Reprint requests: G. David Adamson, Fertility Physicians of Northern California, 540 University Avenue, Suite 200, Palo Alto, California 94301 (FAX: 650-322-1730; E-mail: [email protected]).
1582
proportion within the expected range following laparoscopic treatment (3). In the nonlaparoscopy control group 13/35 conceived: 2 spontaneously and 11 from repeat IVF. This proportion (13/35) is not statistically different than those who conceived after surgery but before IVF (14/29). It would be interesting to know whether it took 11 or more IVF cycles for the 11 conceptions. Not surprisingly, older patients and those with stage 4 disease did not conceive as often, consistent with the literature (3, 4). Extensive endometriosis (American Society for Reproductive Medicine score ⬎71) is associated with reduced pregnancy rates (5). Such disease basically requires at least two of the three following presentations of endometriosis: endometriomas, complete cul de sac obliteration, and extensive dense adhesions. However, it is not clear whether pregnancy rates otherwise decrease with increasing stage of disease, some studies demonstrating a reduction and others not (3, 6, 7). Furthermore, although it is probably self-evident that IVF is of value in advanced disease owing to the very low background pregnancy rate and the tangible rate of success with the procedure, the value of IVF in early-stage disease is as yet unproven. In other words, whereas pregnancies certainly occur quite rapidly with IVF in women with endometriosis or any other diagnosis, it is unclear whether 1 cycle of IVF is comparable to 1 month, 6 months, 2 years, or longer of attempting conception naturally (8). Given the not-different proportions conceiving in the laparoscopy and nonlaparoscopy groups (and therefore similar benefit), the elemental question becomes, “Which treatment has the greatest cost in terms of dollars, time, health risk, and emotional burden?” Undoubtedly this question has different answers for different patients. The impact of the diagnosis of endometriosis on outcomes with IVF treatment is not yet clear. There are no large randomized clinical trials to answer several open issues, and cohort trials have been inconclusive (9). The issue of the value of laparoscopic treatment of endometriosis prior to IVF is admittedly complex and has been addressed by the authors, but their conclusions are not universally shared.
Fertility and Sterility姞 Vol. 84, No. 6, December 2005 Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/05/$30.00 doi:10.1016/j.fertnstert.2005.05.071
This controversy is especially true when endometriomas are present, since there are no randomized trials and cohort data are conflicting (7, 10, 11). It is true that laparoscopy and pathologic diagnosis are necessary to confirm endometriomas, and that treatment must be tailored to the type of endometrioma, with some controversy still existing as to the best approach (12). Fertilization rates may or may not decrease with stage 3 and 4 endometriosis. In the Littman et al. (1) study, 13/19 patients with stage 3 or 4 disease conceived following operative laparoscopy, a very substantial proportion. The literature is not conclusive on this issue (6, 7, 13, 14). So it is not clear whether or not the 8 patients who conceived through IVF following laparoscopic surgery actually benefited from the surgery. It is hoped that the current research in metabolic markers for endometriosis and implantation will lead to better understanding, treatment, and outcomes in the future, but it cannot yet be demonstrated convincingly that surgery improves implantation rates with or without IVF or that it improves pregnancy rates for subsequent IVF cycles. Though the authors believe that the subset of patients who have failed multiple cycles of IVF may harbor a certain type of endometriosis which allows them to benefit from thorough surgical therapy, current data cannot substantiate this conclusion. They acknowledge that the best way to answer these questions is with a prospective randomized controlled trial, admittedly very difficult with surgical questions. Despite these problems with study size and design, which limit the ability to generalize its conclusions, and the impossibility of gaining unanimity based on good evidence regarding the role of surgery relative to IVF, the paper importantly emphasizes the under-utilized role of laparoscopic surgery in management of infertile patients. Indeed, it is generally agreed that laparoscopic surgery can improve pregnancy rates not only for minimal and mild disease, but also for more advanced disease (3, 15). There are several reasons why laparoscopic surgery is less commonly employed today than it has been in the past: higher success rates with IVF, fewer highly skilled laparoscopic surgeons, and relatively poor managed-care insurance reimbursement for laparoscopic surgery. Operative laparoscopy’s role before or after IVF is more complex. There are no sufficiently powered prospective randomized trials evaluating the effect on pregnancy outcome of surgical treatment followed by IVF versus IVF alone. (4, 14) Two small retrospective studies comparing the pregnancy rate after IVF to reoperation showed pregnancy rates 9 –12 months following surgery of 21%–24% (16). Therefore, IVF would seem to be a preferable alternative to repeat surgery for most patients (4). Nevertheless, there may be reason to treat large endometriomas (⬎3 cm), especially if response to ovarian stimulation drugs is poor before surgery (12). However, such surgery can be very difficult and requires a talented surgeon in order to avoid vascular and ovarian injury that might Fertility and Sterility姞
result in even poorer ovarian response postoperatively. The decision to operate is not easy. There may be a benefit of operative laparoscopic surgery for other morphologic presentations of endometriosis prior to IVF, but this has not yet been proven. The optimal approach to managing the infertile endometriosis patient is to perform a comprehensive evaluation, and then develop a treatment plan that progresses from simpler, yet effective and safe, treatments to more complex and costly treatments. The major advantage of laparoscopy performed early on is that it is as effective as 1 or 2 cycles of IVF, does not increase the risk of multiple birth, may help achieve more than 1 pregnancy, and is effective for alleviating pain and removing endometriomas. Its major disadvantages are its cost, the fact that endometriosis might not be found at laparoscopy, the need to take up to 9 –12 months postoperatively to give the operation a reasonable chance to be successful, the relative paucity of skilled surgeons, and surgical risks. The major advantage of IVF is the fact that it treats multiple infertility problems of both the female and male, has a high rate of success on just 1 attempt relative to surgery, and takes only 2–3 months to complete treatment, making it more attractive for older patients. Its major disadvantages are its cost, that it is often not covered by insurance, and the risk of multiple pregnancy. These relative benefits and costs need to be understood and explained to patients before the comprehensive treatment plan is developed. The number needed to treat to obtain 1 additional pregnancy for women undergoing laparoscopy should be estimated and discussed with each patient. Following operative laparoscopy, a realistic estimate of the chances of success needs to be made and discussed with the patient (5). The fact that IVF does not work on every patient the first time, and a life table estimate of success rates for 1, 2, and 3 cycles of IVF, also needs to be discussed with each patient. After informed consent, an individualized treatment plan can be developed, executed and modified as necessary based on patient age, duration of infertility, previous pregnancies, changing clinical conditions, and outcomes of treatment. Such an approach will usually avoid a situation in which IVF is discontinued to undergo an operative laparoscopy. However, in some situations such an approach might well be appropriate and, when indicated, the paper by Littman et al. (1) strongly suggests that a good chance of pregnancy exists when the surgery is properly performed. REFERENCES 1. Littman E, Giudice L, Lathi R, Berkler B, Milki A, Nezhat C. Role of laparoscopic treatment of endometriosis in patients with failed in vitro fertilization cycles. Fertil Steril 2005;84:1574 – 8. 2. Meldrum DR, Silverberg KM, Bustillo M, Stokes L. Success rate with repeated cycles of in vitro fertilization– embryo transfer. Fertil Steril 1998;69:1005–9. 3. Adamson GD, Pasta DJ. Surgical treatment of endometriosis-associated infertility: meta-analysis compared with survival analysis. Am J Obstet Gynecol 1994;171:1488 –505.
1583
4. The Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility. Fertil Steril 2004;81:1441– 6. 5. Adamson GD, Pasta DJ. Pregnancy rates can be predicted by validated endometriosis fertility index (EFI). Fertil Steril 2002;77(Suppl 1):S48. 6. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril 2002;77:1148 –55. 7. Spandorfer SD, Rosenwaks Z. Endometriosis. Is IVF the answer for infertility? Stage-related success rates in 1417 consecutive IVF-ET. Available at: http://www.Kenes.com/controversies/cogi3/abstracts/ 9041.doc; accessed: Nov. 1, 2005. 8. Soliman S, Daya S, Collins J, Jarrell J. A randomized trial of in vitro fertilization versus conventional treatment for infertility. Fertil Steril 1993;59:1239 – 44. 9. Dokras SA, Olive DL. Endometriosis and assisted reproductive technologies. Clin Obstet Gynecol 1999;42:687–98. 10. Garcia-Velasco JA, Mahutte NG, Corona J, Zuniga V, Giles J, Arici A, Pellicer A. Removal of endometriomas before in vitro fertilization does not improve fertility outcomes: a matched, case-control study. Fertil Steril 2004;81:1194 –7. 11. Wong BC, Gillman NC, Oehninger S, Gibbons WE, Stadtmauer LA.
1584
Adamson
Laparoscopy, IVF, endometriosis: enigma
12.
13.
14.
15.
16.
Results of in vitro fertilization in patients with endometriomas: is surgical removal beneficial? Am J Obstet Gynecol 2004;191:597– 606; discussion 606 –7. Canis M, Pouly JL, Tamburro S, Mage G, Wattiez A, Bruhat MA. Ovarian response during IVF-embryo transfer cycles after laparoscopic ovarian cystectomy for endometriotic cysts of ⬎3 cm in diameter. Hum Reprod 2001;16:2583– 6. Guzick DS, Silliman NP, Adamson GD, Buttram VC, Canis M, Malinak LR, Schenken RS. Prediction of pregnancy in infertile women based on the American Society for Reproductive Medicine’s revised classification of endometriosis. Fertil Steril 1997;67:822–9. Aboulghar MA, Mansour RT, Serour GI, Al-Inany HG, Aboulghar MM. The outcome of in vitro fertilization in advanced endometriosis with previous surgery: a case-controlled study. Am J Obstet Gynecol 2003;188:371–5. Jacobson TZ, Barlow DH, Koninckx PR, Olive D, Farquhar C. Laparoscopic surgery for subfertility associated with endometriosis. Cochrane Database Syst Rev 2002;:CD001398. Cheewadhanaraks S. Comparison of fecundity after second laparotomy for endometriosis to in vitro fertilization and embryo transfer. J Med Assoc Thai 2004;87:361– 6.
Vol. 84, No. 6, December 2005