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Surgery for ectopic pregnancy: making the right choice
Comment
Surgery for ectopic pregnancy: making the right choice surgical skills or personal preferences might account for why the recommendation to attempt a salpingotomy in cases of contralateral tubal pathology was only applied in 30% of eligible women in a Dutch survey,4 a third of whom were converted to salpingectomy, resulting in a successful salpingotomy rate of only 21%. Second, ESEP was not powered to detect a difference in cumulative ongoing pregnancy rate lower than 15% after salpingotomy compared with salpingectomy, even after the data were pooled in a meta-analysis.2,3 In a large prospective cohort study in France,5 cumulative intrauterine pregnancy rate within 24 months was 9% higher after salpingotomy than after salpingectomy (76% vs 67%). This difference became significant, after multivariate analysis, in women older than 35 years and in those with a history of infertility or tubal disease, in line with other data.5–7 In ESEP, a prespecified subgroup analysis showed no beneficial effect by maternal age (<31 vs ≥31 years; p=0·56), but the age groups compared were different from the French cohort study (≤35 or >35 years).2,5 In our opinion, a difference in spontaneous cumulative intrauterine pregnancy rate of 9% is clinically relevant.5 It should also be taken into account that, after salpingectomy, women can be more dependent on assisted reproductive technology to achieve an intrauterine pregnancy than after salpingotomy.8 Third, with respect to short-term tubal complications, in ESEP, the persistent trophoblast was, unsurprisingly,
Published Online February 3, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60129-X See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(14)60123-9
Dr Najeeb Layyous/Science Photo Library
Currently, the most widely accepted treatment options for tubal ectopic pregnancies are laparoscopic surgery or systemic medical treatment with methotrexate.1 When laparoscopic surgery is indicated, either salpingotomy (ie, conserving the fallopian tube and removing only the trophoblast) or salpingectomy (ie, complete removal of the fallopian tube) can be used. When compared with salpingectomy, salpingotomy might better protect future fertility, but with an increased risk of persistent trophoblast or recurrent ectopic pregnancy. In The Lancet, Femke Mol and colleagues2 report the results of the European Surgery in Ectopic Pregnancy (ESEP) study, in which 446 women with laparoscopically proven tubal pregnancy and a normal contralateral tube were randomly assigned to undergo either salpingotomy or salpingectomy. The investigators were unable to confirm their primary hypothesis that the cumulative ongoing pregnancy rate after spontaneous conception at 36 months of follow-up was at least 15% higher after salpingotomy than after salpingectomy, either in the intention-totreat (60·7% vs 56·2%, p=0·678) or per-protocol analysis (62·3% vs 56·2%, p=0·492). They report that persistent trophoblast occurred more frequently in the salpingotomy group (14 [7%] of 215) than in the salpingectomy group (1 [<1%] of 231; relative risk [RR] 15·0, 95% CI 2·0–113·4), although the risk of repeat ectopic pregnancy was similar in both groups (18 [8%] vs 12 [5%]; RR 1·6, 0·8–3·3). The investigators also did an updated meta-analysis with results from one other study. They conclude that, because salpingotomy did not improve fertility prospects over salpingectomy, salpingectomy should be the preferred surgical treatment for ectopic pregancy.2,3 Although we appreciate the high methodological quality of ESEP, we challenge the investigators’ conclusion that salpingectomy should be preferred over salpingotomy in women eligible for conservative surgical management of ectopic pregnancy for several reasons. First, ESEP did not to take the quality of salpingotomy into account. The investigators gathered no information about surgical experience, did not do tubal patency testing after surgery, did not record whether intrauterine pregnancies occurred via the ipsilateral or heterolateral tube, and did not attempt to account for why repeat ipsilateral tubal ectopic pregnancies were still reported after salpingectomy. Poor
Tubal pregnancy
www.thelancet.com Published online February 3, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60129-X
1
Comment
more common in the salpingotomy group than in the salpingectomy group, with the reported frequency similar to the 6% reported elsewhere.5 In our opinion, persistent trophoblast can usually be managed safely and effectively by methotrexate treatment, as advised by international guidance,9 and the choice between salpingotomy and salpingectomy should be based on shared decision making between patient and doctor, taking into account the balance between the possible burden of the additional treatment for persistent trophoblast and the possibility of better future pregnancy prospects after salpingotomy. In a study of patients’ preferences10 by the same research group, which included a subset of the women enrolled into ESEP, the risk of persistent trophoblast after salpingotomy was acceptable to patients if compensated by a small improvement in the spontaneous intrauterine pregnancy rate. Therefore we postulate that, in women older than 35 years old or in women with a history of infertility or tubal disease, an 8–10% clinically relevant increase in cumulative intrauterine pregnancy rate, as seen in the French cohort study,5 would outweigh the 6–7% increase in persistent trophoblast after salpingotomy compared with salpingectomy.2 Finally, for longer-term tubal complications, ESEP showed that the risk of repeat ectopic pregnancy was similar after salpingotomy and salpingectomy. In the study of patients’ preferences,10 the a priori preference for salpingotomy as the surgical treatment of choice for ectopic pregnancy in subfertile women naive to either procedure (88% [38/43]) and in women who underwent salpingotomy in ESEP (78% [18/23]) was high, by contrast with women who underwent salpingectomy in ESEP (48% [13/27]). After a discrete choice experiment in this study—designed to determine the trade-offs women make between hypothetically improved cumulative ongoing pregnancy rate against risks of persistent trophoblast and repeat ectopic pregnancy—patients showed a stronger preference towards salpingectomy than expected from the a priori preference results. The ESEP investigators argue that the most important decisive factor for this preference switch seemed to be the patient’s wish to reduce the risk of repeat ectopic pregnancy2,10—a risk that has not been confirmed in ESEP or elsewhere.2,3 We therefore question the relevance of this finding to their argument in favour of salpingectomy. 2
In practice, we propose that in women with ectopic pregnancy and an indication for laparoscopic surgery, salpingotomy should be preferred if the contralateral tube is abnormal because cumulative intrauterine pregnancy rate is higher than after salpingectomy.8,11,12 Salpingotomy should also be offered to women with normal contralateral tubes, especially if they are older than 35 years or have a history of infertility, since from a patient’s perspective the benefits (increased cumulative intrauterine pregnancy rate) outweigh the risks (increased persistent trophoblast).5 For women younger than 35 years with normal contralateral tubes and without a history of infertility or tubal disease, shared decision making between patient and doctor should be based on surgical experience, and the potential benefits and risks of both techniques.2,5,8 *Thomas D’Hooghe, Carla Tomassetti Leuven University Fertility Centre, Department Obstetrics and Gynecology, University Hospital Gasthuisberg, and Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven, 3000 Leuven, Belgium [email protected] TD’H has received research funding from Ferring Pharmaceuticals, Merck Sorono, and Besins Healthcare, and has been a consultant for Roche Diagnostics, Proteomika, Bayer, Astellas Pharma, Actavis (Uteron), Pharmaplex, Teva, Arresto, and Merck. CT declares that she has no conflicts of interest. 1
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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. Mol F, van Mello NM, Strandell A, et al. Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP study): an open-label, multicentre, randomised controlled trial. Lancet 2014; published online Feb 3. http://dx. doi.org/10.1016/S0140-6736(14)60123-9. Fernandez H, Capmas P, Lucot JP, et al. Fertility after ectopic pregnancy: the DEMETER randomized trial. Hum Reprod 2013; 28: 1247–53. Mol F, van den Boogaard E, van Mello NM, et al. Guideline adherence in ectopic pregnancy management. Hum Reprod 2011; 26: 307–15. de Bennetot M, Rabischong B, Aublet-Cuvelier B, et al. Fertility after tubal ectopic pregnancy: results of a population-based study. Fertil Steril 2012; 98: 1271–76. Ego A, Subtil D, Cosson M, et al. Survival analysis of fertility after ectopic pregnancy. Fertil Steril 2001; 75: 560–66. Becker S, Solomayer E, Hornung R, et al. Optimal treatment for patients with ectopic pregnancies and a history of fertility-reducing factors. Arch Gynecol Obstet 2011; 283: 41–46. Mol BW, Matthijsse HC, Tinga DJ, et al. Fertility after conservative and radical surgery for tubal pregnancy. Hum Reprod 1998; 13: 1804–09. Guidelines and Audit Committee of the Royal College of Obstetricians and Gynaecologists. Green-top guideline number 21: the management of tubal pregnancy. London: Royal College of Obstetricians and Gynaecologists, 2004. van Mello NM, Mol F, Opmeer BC, et al. Salpingotomy or salpingectomy in tubal ectopic pregnancy: what do women prefer? Reprod Biomed Online 2010; 21: 687–93. Dubuisson JB, Morice P, Chapron C, et al. Salpingectomy—the laparoscopic surgical choice for ectopic pregnancy. Hum Reprod 1996; 11: 1199–203. Silva PD, Schaper AM, Rooney B. Reproductive outcome after 143 laparoscopic procedures for ectopic pregnancy. Obstet Gynecol 1993; 81: 710–15.
www.thelancet.com Published online February 3, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60129-X
Surgery for ectopic pregnancy: making the right choice surgical skills or personal preferences might account for why the recommendation to attempt a salpingotomy in cases of contralateral tubal pathology was only applied in 30% of eligible women in a Dutch survey,4 a third of whom were converted to salpingectomy, resulting in a successful salpingotomy rate of only 21%. Second, ESEP was not powered to detect a difference in cumulative ongoing pregnancy rate lower than 15% after salpingotomy compared with salpingectomy, even after the data were pooled in a meta-analysis.2,3 In a large prospective cohort study in France,5 cumulative intrauterine pregnancy rate within 24 months was 9% higher after salpingotomy than after salpingectomy (76% vs 67%). This difference became significant, after multivariate analysis, in women older than 35 years and in those with a history of infertility or tubal disease, in line with other data.5–7 In ESEP, a prespecified subgroup analysis showed no beneficial effect by maternal age (<31 vs ≥31 years; p=0·56), but the age groups compared were different from the French cohort study (≤35 or >35 years).2,5 In our opinion, a difference in spontaneous cumulative intrauterine pregnancy rate of 9% is clinically relevant.5 It should also be taken into account that, after salpingectomy, women can be more dependent on assisted reproductive technology to achieve an intrauterine pregnancy than after salpingotomy.8 Third, with respect to short-term tubal complications, in ESEP, the persistent trophoblast was, unsurprisingly,
Published Online February 3, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60129-X See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(14)60123-9
Dr Najeeb Layyous/Science Photo Library
Currently, the most widely accepted treatment options for tubal ectopic pregnancies are laparoscopic surgery or systemic medical treatment with methotrexate.1 When laparoscopic surgery is indicated, either salpingotomy (ie, conserving the fallopian tube and removing only the trophoblast) or salpingectomy (ie, complete removal of the fallopian tube) can be used. When compared with salpingectomy, salpingotomy might better protect future fertility, but with an increased risk of persistent trophoblast or recurrent ectopic pregnancy. In The Lancet, Femke Mol and colleagues2 report the results of the European Surgery in Ectopic Pregnancy (ESEP) study, in which 446 women with laparoscopically proven tubal pregnancy and a normal contralateral tube were randomly assigned to undergo either salpingotomy or salpingectomy. The investigators were unable to confirm their primary hypothesis that the cumulative ongoing pregnancy rate after spontaneous conception at 36 months of follow-up was at least 15% higher after salpingotomy than after salpingectomy, either in the intention-totreat (60·7% vs 56·2%, p=0·678) or per-protocol analysis (62·3% vs 56·2%, p=0·492). They report that persistent trophoblast occurred more frequently in the salpingotomy group (14 [7%] of 215) than in the salpingectomy group (1 [<1%] of 231; relative risk [RR] 15·0, 95% CI 2·0–113·4), although the risk of repeat ectopic pregnancy was similar in both groups (18 [8%] vs 12 [5%]; RR 1·6, 0·8–3·3). The investigators also did an updated meta-analysis with results from one other study. They conclude that, because salpingotomy did not improve fertility prospects over salpingectomy, salpingectomy should be the preferred surgical treatment for ectopic pregancy.2,3 Although we appreciate the high methodological quality of ESEP, we challenge the investigators’ conclusion that salpingectomy should be preferred over salpingotomy in women eligible for conservative surgical management of ectopic pregnancy for several reasons. First, ESEP did not to take the quality of salpingotomy into account. The investigators gathered no information about surgical experience, did not do tubal patency testing after surgery, did not record whether intrauterine pregnancies occurred via the ipsilateral or heterolateral tube, and did not attempt to account for why repeat ipsilateral tubal ectopic pregnancies were still reported after salpingectomy. Poor
Tubal pregnancy
www.thelancet.com Published online February 3, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60129-X
1
Comment
more common in the salpingotomy group than in the salpingectomy group, with the reported frequency similar to the 6% reported elsewhere.5 In our opinion, persistent trophoblast can usually be managed safely and effectively by methotrexate treatment, as advised by international guidance,9 and the choice between salpingotomy and salpingectomy should be based on shared decision making between patient and doctor, taking into account the balance between the possible burden of the additional treatment for persistent trophoblast and the possibility of better future pregnancy prospects after salpingotomy. In a study of patients’ preferences10 by the same research group, which included a subset of the women enrolled into ESEP, the risk of persistent trophoblast after salpingotomy was acceptable to patients if compensated by a small improvement in the spontaneous intrauterine pregnancy rate. Therefore we postulate that, in women older than 35 years old or in women with a history of infertility or tubal disease, an 8–10% clinically relevant increase in cumulative intrauterine pregnancy rate, as seen in the French cohort study,5 would outweigh the 6–7% increase in persistent trophoblast after salpingotomy compared with salpingectomy.2 Finally, for longer-term tubal complications, ESEP showed that the risk of repeat ectopic pregnancy was similar after salpingotomy and salpingectomy. In the study of patients’ preferences,10 the a priori preference for salpingotomy as the surgical treatment of choice for ectopic pregnancy in subfertile women naive to either procedure (88% [38/43]) and in women who underwent salpingotomy in ESEP (78% [18/23]) was high, by contrast with women who underwent salpingectomy in ESEP (48% [13/27]). After a discrete choice experiment in this study—designed to determine the trade-offs women make between hypothetically improved cumulative ongoing pregnancy rate against risks of persistent trophoblast and repeat ectopic pregnancy—patients showed a stronger preference towards salpingectomy than expected from the a priori preference results. The ESEP investigators argue that the most important decisive factor for this preference switch seemed to be the patient’s wish to reduce the risk of repeat ectopic pregnancy2,10—a risk that has not been confirmed in ESEP or elsewhere.2,3 We therefore question the relevance of this finding to their argument in favour of salpingectomy. 2
In practice, we propose that in women with ectopic pregnancy and an indication for laparoscopic surgery, salpingotomy should be preferred if the contralateral tube is abnormal because cumulative intrauterine pregnancy rate is higher than after salpingectomy.8,11,12 Salpingotomy should also be offered to women with normal contralateral tubes, especially if they are older than 35 years or have a history of infertility, since from a patient’s perspective the benefits (increased cumulative intrauterine pregnancy rate) outweigh the risks (increased persistent trophoblast).5 For women younger than 35 years with normal contralateral tubes and without a history of infertility or tubal disease, shared decision making between patient and doctor should be based on surgical experience, and the potential benefits and risks of both techniques.2,5,8 *Thomas D’Hooghe, Carla Tomassetti Leuven University Fertility Centre, Department Obstetrics and Gynecology, University Hospital Gasthuisberg, and Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven, 3000 Leuven, Belgium [email protected] TD’H has received research funding from Ferring Pharmaceuticals, Merck Sorono, and Besins Healthcare, and has been a consultant for Roche Diagnostics, Proteomika, Bayer, Astellas Pharma, Actavis (Uteron), Pharmaplex, Teva, Arresto, and Merck. CT declares that she has no conflicts of interest. 1
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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. Mol F, van Mello NM, Strandell A, et al. Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP study): an open-label, multicentre, randomised controlled trial. Lancet 2014; published online Feb 3. http://dx. doi.org/10.1016/S0140-6736(14)60123-9. Fernandez H, Capmas P, Lucot JP, et al. Fertility after ectopic pregnancy: the DEMETER randomized trial. Hum Reprod 2013; 28: 1247–53. Mol F, van den Boogaard E, van Mello NM, et al. Guideline adherence in ectopic pregnancy management. Hum Reprod 2011; 26: 307–15. de Bennetot M, Rabischong B, Aublet-Cuvelier B, et al. Fertility after tubal ectopic pregnancy: results of a population-based study. Fertil Steril 2012; 98: 1271–76. Ego A, Subtil D, Cosson M, et al. Survival analysis of fertility after ectopic pregnancy. Fertil Steril 2001; 75: 560–66. Becker S, Solomayer E, Hornung R, et al. Optimal treatment for patients with ectopic pregnancies and a history of fertility-reducing factors. Arch Gynecol Obstet 2011; 283: 41–46. Mol BW, Matthijsse HC, Tinga DJ, et al. Fertility after conservative and radical surgery for tubal pregnancy. Hum Reprod 1998; 13: 1804–09. Guidelines and Audit Committee of the Royal College of Obstetricians and Gynaecologists. Green-top guideline number 21: the management of tubal pregnancy. London: Royal College of Obstetricians and Gynaecologists, 2004. van Mello NM, Mol F, Opmeer BC, et al. Salpingotomy or salpingectomy in tubal ectopic pregnancy: what do women prefer? Reprod Biomed Online 2010; 21: 687–93. Dubuisson JB, Morice P, Chapron C, et al. Salpingectomy—the laparoscopic surgical choice for ectopic pregnancy. Hum Reprod 1996; 11: 1199–203. Silva PD, Schaper AM, Rooney B. Reproductive outcome after 143 laparoscopic procedures for ectopic pregnancy. Obstet Gynecol 1993; 81: 710–15.
www.thelancet.com Published online February 3, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60129-X