UvA-DARE (Digital Academic Repository) Surgical management of tubal pregnancy Mol, Femke. Link to publication

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1 UvA-DARE (Digital Academic Repository) Surgical management of tubal pregnancy Mol, Femke Link to publication Citation for published version (APA): Mol, F. (2013). Surgical management of tubal pregnancy General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 06 Jul 2018

2 5 Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP trial): a randomised controlled trial Femke Mol, Norah M. van Mello, Annika Strandell, Karin Strandell, Davor Jurkovic, Jackie Ross, Kurt T. Barnhart, Tamer M. Yalcinkaya Harold R. Verhoeve, Peppino C. M. Graziosi, Carolien A. M. Koks Ingmar Klinte, Lars Hogström, Ineke C.A.H. Janssen, Harry Kragt, Annemieke Hoek, Trudy C.M. Trimbos-Kemper, Frank J.M. Broekmans Wim N.P. Willemsen, Willem M. Ankum, Ben W. Mol, Madelon van Wely Fulco van der Veen, Petra J. Hajenius for the European Surgery in Ectopic Pregnancy (ESEP) study group Submitted

3 CHAPTER 5 ABSTRACT BACKGROUND: In women with tubal pregnancy it is uncertain whether salpingotomy offers better fertility prospects over salpingectomy. Salpingotomy preserves the tube, but bears the risks of persistent trophoblast and repeat tubal pregnancy. Salpingectomy minimizes these risks, but leaves only one tube available for conception. METHODS: We randomly assigned women with a laparoscopically confirmed tubal pregnancy and a normal contralateral tube to salpingotomy or to salpingectomy. The primary outcome measure was ongoing pregnancy by natural conception. Differences in cumulative ongoing pregnancy rates were expressed as a Fecundity Rate Ratio with 95% confidence interval (CI), calculated through Cox proportional hazard analysis with a time horizon of 36 months. Secondary outcomes measures were persistent trophoblast and repeat ectopic pregnancy and were expressed as Rate Ratios with 95% confidence intervals. We also performed a meta-analysis that included our trial. FINDINGS: A total of 446 women were randomised. The cumulative ongoing pregnancy rate was 60.7% after salpingotomy and 56.2% after salpingectomy (Fecundity Rate Ratio 1.06; 95% CI, 0.81 to 1.4; Log rank test P value 0.678). Persistent trophoblast occurred more frequent in the salpingotomy group than in the salpingectomy group (14 (7.0%) versus 1 (0.4%); Rate Ratio 15; 95% CI 2.0 to 113). Repeat ectopic pregnancy occurred in 18 women (8.4%) in the salpingotomy group versus 12 (5.2%) in the salpingectomy group (Rate Ratio 1.6; 95% CI 0.80 to 3.3). An updated meta-analysis with one other study confirmed these results. INTERPRETATION: In women with a tubal pregnancy and a normal contralateral tube, salpingotomy does not improve fertility prospects over salpingectomy (International Standard Randomised Controlled Trials Number ). FUNDING: Supported by grants of The Netherlands Organisation for Health Research and Development (ZonMw grants and ) and of The Health & Medical Care Committee of the Region Västra Götaland, Sweden. 80

4 FERTILITY AFTER SALPINGOTOMY AND SALPINGECTOMY INTRODUCTION Approximately 1-2% of all pregnancies are ectopic (1). Most ectopic pregnancies are located in the Fallopian tube, and surgery is a frequently applied treatment (2). Excision of the affected tube, i.e. salpingectomy, is considered the standard surgical procedure (3-5). As far back as 1914, Beckwith Whitehouse questioned whether it was justified to sacrifice the tube on all occasions. After having studied the histopathology of tubal pregnancies, he was the first to show that salpingotomy was also feasible, as he removed the pregnancy from the tube, leaving the affected tube in situ (6). From 1957 onwards, this concept of preservation of the affected organ was propagated over ablative surgery in view of future reproductive capacity (7). Although randomised studies were lacking, salpingotomy was widely adopted, assuming a positive effect on reproductive outcome, while accepting the potential drawback of a repeat ectopic pregnancy in the same tube (8). In 1984, another disadvantage of salpingotomy was reported; the incomplete removal of the ectopic pregnancy, i.e. persistent trophoblast, necessitating additional treatment (9). At present, it still is unclear whether salpingotomy provides better fertility prospects compared to salpingectomy and whether the presumed potential benefit outweighs the disadvantages. In view of this uncertainty, we initiated a randomised controlled trial, -the European Surgery in Ectopic Pregnancy (ESEP) study- comparing salpingotomy and salpingectomy with respect to future fertility prospects. We investigated whether salpingotomy would improve ongoing pregnancy rates by natural conception compared to salpingectomy. 5 METHODS Participants From September 2004 through November 2011, we performed a randomised controlled trial in The Netherlands, Sweden, the United Kingdom and the United States. The study was performed in university hospitals and teaching as well as non-teaching hospitals. The study originally started as a Dutch-Swedish-British collaboration. During the study period, two centres in the United States joined the collaboration. One institutional review board in each country approved the study protocol, after which the board of directors of other centres approved local execution of the study. Women were eligible for the trial if they had a presumptive diagnosis of tubal pregnancy and were scheduled for surgery. To reach this presumptive diagnosis, an algorithm based on transvaginal sonography with serum hcg measurements was followed in all clinics, as recommended by (inter)national guidelines (3-5,10). Women who were younger than 18 years of age, were hemodynamically unstable, had no desire for future pregnancy, were 81

5 CHAPTER 5 pregnant after in vitro fertilisation (IVF) were excluded, as were women with a pregnancy in a solitary tube, or with contralateral tubal occlusion or a hydrosalpinx documented at a previous hysterosalpingography or laparoscopy. Participating women provided written informed consent for randomisation before surgery. At surgery, the presence of a tubal pregnancy had to be confirmed. If tubal rupture was present, women were still eligible for the trial as long as the tubal rupture did not interfere with the possibility to perform a salpingotomy. Women were not eligible if the condition of the contralateral tube, according to the surgeon, rendered future pregnancy unlikely in case the assigned treatment would be salpingectomy (e.g., hydrosalpinx, severe peri tubal adhesions or malformations). Thus, only women with a tubal pregnancy amenable to either treatment interventions, in the presence of a normal contralateral tube, were enrolled in the trial. Procedures During surgery, after confirmation of the diagnosis tubal pregnancy and after having established visually that the contralateral tube was normal, consenting women were randomly assigned to salpingotomy or salpingectomy using a central internet-based randomisation program. The randomisation sequence was computer-generated with the online randomisation program. Randomisation was stratified by hospital, the woman s age (<35 or 35 years) and history of tubal pathology (i.e. previous ectopic pregnancy, tubal surgery or pelvic inflammatory disease). The randomisation sequence was not accessible by the recruiters. The allocation code was disclosed after the patient s initials were entered and inclusion criteria were confirmed on the website; the unique number generated could not be deleted afterwards. This study was open-label because the nature of the intervention meant that masking to interventions was not possible. Both interventions were performed following local procedural standards used in the participating hospitals. In women assigned to salpingotomy, a linear salpingotomy was performed. To prevent bleeding, an injection of epinephrine, terlipressine (Glypressin ), ornipressin (POR-8 ) or any analogue, or the application of fibrin glue (Tissue Coll ) was allowed. In women assigned to salpingectomy, all techniques for complete salpingectomy were allowed including clamping, cutting and suturing, use of a bipolar forceps and scissors, use of a bipolar cutting forceps (Cutting forceps, ACMI USA), vessel seal instrument (Ligasure, Covidien USA), ultrasonic device (Harmonic Ace, Ethicon USA), or endoloop snare (Endoloop, Johnson and Johnson USA). Whenever necessary, salpingotomy was converted to salpingectomy and laparoscopy was converted to open surgery. After surgery, all women were informed about their study group assignment and what intervention they received. To identify persistent trophoblast, serum hcg was measured post-operatively until undetectable levels were reached in both study groups. Serum hcg concentrations were expressed in IU/L (conversion factor to SI unit, 1.00 according to the World Health Organisation Third International Standard 75/537) (11). To assess fertility after 82

6 FERTILITY AFTER SALPINGOTOMY AND SALPINGECTOMY surgery, women were contacted by telephone, or postal mail every six months by the researchers. A questionnaire was completed comprising the occurrence and outcome of subsequent pregnancies until an ongoing pregnancy occurred. Repeated attempts by telephone, or postal mail were made when women did not respond by the initial follow-up. Outcomes Primary outcome measure was ongoing pregnancy by natural conception. An ongoing pregnancy was defined as an intra-uterine pregnancy visible at ultrasound at a gestational age of 12 weeks with fetal cardiac activity, or a pregnancy resulting in the delivery of a child. We calculated the time to the first ongoing pregnancy in months, from the date of surgery of the tubal pregnancy to the first day of the last menstrual period before the conception leading to the ongoing pregnancy. If an ongoing pregnancy did not occur, followup ended at the last date of contact, or at the moment when either IVF or reconstructive tubal surgery was performed. Natural conceptions that occurred after failed IVF treatment were registered, but these pregnancies were not considered as endpoint in the initial analysis. Secondary outcome measures were persistent trophoblast, first repeat ectopic pregnancy and first ongoing pregnancy after ovulation induction, intra uterine insemination or IVF. Persistent trophoblast was defined as rising or plateauing serum hcg concentrations postoperatively necessitating systemic methotrexate treatment or surgical intervention.10 Repeat ectopic pregnancy was defined as any ectopic pregnancy or a persisting pregnancy of unknown location for which surgical or medical treatment with methotrexate was installed. 5 Statistical analysis The ongoing pregnancy rate after salpingectomy was assumed to be 40% after 36 months with a median time to ongoing pregnancy of 1.4 years (12). We considered a 15% increase of the ongoing pregnancy rate after salpingotomy from 40% to 55% to be clinically relevant so as to overcome the potential disadvantages of persistent trophoblast and repeat ectopic pregnancy. This increase corresponded with a 40% reduction of the median time to ongoing pregnancy from 1.4 to 1.0 year. We needed to enrol 404 women for a power of 80% at a significance level of 0.05 (2-sided test). Since we anticipated a loss to follow up rate of 10%, we aimed to enrol 450 women (13). The analysis was performed according to the intention to treat principle. The cumulative ongoing pregnancy rates were derived from life table analysis and differences were expressed as a Fecundity Rate Ratio with 95% confidence interval calculated through Cox proportional hazard analysis with a time horizon of 36 months. Kaplan-Meier curves were constructed, estimating the cumulative probability of an ongoing pregnancy over time. The log-rank test was used to test differences between the Kaplan-Meier curves for statistical significance. Persistent trophoblast, repeat ectopic pregnancy and ongoing pregnancies 83

7 CHAPTER 5 after ovulation induction, intra uterine insemination or IVF were expressed as a Rate Ratio with 95% confidence intervals. A per protocol analysis on the primary outcome measure was performed in women who underwent the assigned salpingotomy, i.e. who did not have a conversion to salpingectomy, compared to women who had been randomly assigned to salpingectomy. Prespecified subgroup analyses were planned on the variables maternal age, history of a previous ectopic pregnancy, pre-operative serum hcg concentration and size of the ectopic pregnancy on ultrasound. The continuous variables were dichotomized using medians. In each subgroup, Fecundity Rate Ratios with 95% confidence intervals were calculated with Cox proportional hazard analysis. Interactions between these co-variables and assigned treatment on time to ongoing pregnancy were studied. A P value of less than 0.05 was considered to indicate interaction. All statistical analyses were done in STATA (version 11.2). Role of the funding source This study was supported by The Netherlands Organisation for Health Research and Development (ZonMW) and The Health & Medical Care Committee of the Region Västra Götaland, Sweden. The sponsors were not involved in the preparation of the study protocol, management of the trial, analysis of the data, or preparation of the manuscript. All authors vouch for the accuracy and completeness of the reported data. 450 Women with tubal ectopic pregnancy were enrolled 446 Women underwent randomiza on 4 Were excluded owing to inability to provide data 215 Were assigned to salpingotomy 164 Received assigned interven on 51 Received salpingectomy 43 Had conversion due to persistent bleeding 3 Had a re-interven on 5 Had persistent trophoblast 231 Were assigned to salpingectomy 231 Received assigned interven on 11 Were lost to fer lity follow up 13 Were lost to fer lity follow up 215 Were included in the inten on-to-treat analysis 164 Were included in the Per Protocol analysis 231 Were included in the intern on-to-treat analysis 231 Were included in the Per Protocol analysis Figure 1. Number of Women Who Were Enrolled, Randomly Assigned to a Treatment Group, and Included in the Analyses. 84

8 FERTILITY AFTER SALPINGOTOMY AND SALPINGECTOMY RESULTS A total of 450 women were enrolled in the study. Four women from one hospital were excluded after randomisation (three were allocated salpingotomy and on salpingectomy) owing to the inability of that hospital to provide any data on these women. The remaining 446 women were randomly assigned to treatment at 32 centres (median accrual per centre, 9 women; range 1 to 71), 215 to salpingotomy and 231 to salpingectomy (Fig. 1). In February 2013 the trial was ended. Twenty-four women (5.4%) were lost to fertility follow-up, 11 (5.1%) in the salpingotomy group and 13 (5.6%) in the salpingectomy group (P value 0.82). The total follow-up time was 7,794 months (3,563 months after salpingotomy, 4,231 months after salpingectomy, P value 0.18). Of the 215 women in the salpingotomy group, 164 (76%) underwent the assigned intervention as planned, while 51 women received salpingectomy. In 43 women a conversion to salpingectomy during the initial surgery was necessary because of persistent tubal bleeding, three women had a salpingectomy at re-intervention because of suspected tubal bleeding and five women had a salpingectomy because of persistent trophoblast. Baseline characteristics were comparable across the study groups (Table 1). Adverse events, such as conversion to laparotomy or salpingectomy, blood transfusions, re-admittances and reinterventions, are shown in Table 2. The outcomes are summarised in Table 3. Of the 446 women who underwent randomisation and were analysed, 222 had an ongoing pregnancy by natural conception; 108 after salpingotomy and 114 after salpingectomy. The cumulative ongoing pregnancy rate by natural conception was 60.7% after salpingotomy and 56.2% after salpingectomy within a time horizon of 36 months (Fecundity Rate Ratio 1.06; 95% CI 0.81 to 1.4), Log rank test P value (Fig. 2). Persistent trophoblast occurred more frequent in the salpingotomy group than in the salpingectomy group (14 (6.5%) versus 1 (0.4%); Rate Ratio 15; 95% CI 2.0 to 113). Repeat ectopic pregnancy occurred in 18 women (8.4%) in the salpingotomy group versus 12 (5.2%) in the salpingectomy group (Rate Ratio 1.6; 95% CI 0.80 to 3.3). There were seven ongoing pregnancies after IVF in the salpingotomy group, while in the salpingectomy group there were three ongoing pregnancies after ovulation induction, one after intra uterine insemination and two after IVF (Table 3). 5 The Per Protocol analysis incorporated 164 women with completed salpingotomy and the 231 women assigned to salpingectomy. Two hundred and one women had an ongoing pregnancy by natural conception; 87 after salpingotomy and 114 after salpingectomy. The cumulative ongoing pregnancy rate by natural conception was 62.3% after salpingotomy and 56.2% after salpingectomy (Fecundity Rate Ratio 1.10; 95% CI 0.83 to 1.5; Log rank test P value 0.492). 85

9 CHAPTER 5 Table 1. Baseline characteristics of the women.* Age Salpingotomy N=215 Salpingectomy N=231 Mean-yr 30.9 ± ± yr no. (%) 110 (51.2) 118 (51.1) Risk factors tubal pathology Known tubal pathology a no. (%) 6 (2.8) 4 (1.7) History of Chlamydia no. (%) 26 (12.1) 22 (9.5) History of PID no. (%) 5 (2.3) 9 (3.9) History of ectopic pregnancy no. (%) 9 (4.2) 5 (2.2) History of Termination of Pregnancy no. (%) 41 (19.1) 54 (23.4) IUD in situ no. (%) 3 (1.4) 2 (0.9) Symptoms None no. (%) 13 (6.1) 10 (4.3) Pelvic pain only no. (%) 38 (17.7) 34 (14.7) Vaginal bleeding only no. (%) 24 (11.2) 25 (10.8) Pelvic pain and vaginal bleeding no. (%) 138 (64.2) 155 (67.1) Ultrasound findings Ectopic mass no. (%) 139 (64.7) 154 (66.7) Size ectopic mass b mean -cm 2.6 ± ±1.4 Fetal heart beat present no. (%) 18 (8.4) 26 (11.2) Pre-operative serum hcg Median IU/L 2,182 (860; 4,298) 2,409 (920; 6,036) Location tubal pregnancy at surgery Ampulla no. (%) 163 (75.8) 177 (76.6) Fimbriae no. (%) 14 (6.5) 26 (11.3) Isthmus no. (%) 31 (14.4) 22 (9.5) Tubal ruture present during surgery c 0 1 (0.4) * Plus-minus values are means ± SD. Medians are with 25th and 75th percentile. a Tubal pathology seen on previous hysterosalpingography or laparoscopy. b The size of the ectopic mass was registered in 254 of 293 women (86.7%) with an ectopic mass seen on ultrasound. c The condition of the woman at forehand did not interfere with salpingotomy. No statistically significant imbalances were observed. 86

10 FERTILITY AFTER SALPINGOTOMY AND SALPINGECTOMY Table 2: (Serious) adverse events. Salpingotomy N = 215 Salpingectomy N = 231 Conversion to open surgery no. (%) 3 (1.4) 3 (1.3) Conversion to salpingectomy no. (%) 43 (20) n.a. Re-laparoscopy with salpingectomy for suspected bleeding no. (%) 2 (0.9) n.a. Blood transfusion no. (%) 14 (6.5) 7 (3) Re-admission only no. (%) 10 (4.7) 3 (1.3) Re-admission with surgical re-intervention no. (%) 5 (2.3) 2 (0.9) Table 3. Primary and Secondary Outcomes. Primary outcome Salpingotomy Salpingectomy Fecundity Rate Ratio (95% CI) Intention-to-treat population No. of women P Value Ongoing pregnancy by natural conception no. (%) a 108 (60.7) 114 (56.2) 1.06 (0.81 to 1.4) b Per Protocol population* No. of women Ongoing pregnancy by natural conception no. (%) a 87 (62.3) 114 (56.2) 1.10 (0.83 to 1.5) b 5 Secondary outcomes Relative Risk (95% CI) Persistent trophoblast no. (%) 14 (7.0) 1 (0.4) 15.0 (2.0 to 113) Repeat ectopic pregnancy no. (%) 18 (8.4) 12 (5.2) 1.6 (0.80 to 3.3) ipsilateral tube 7 (3.3) 3 (1.3) 2.5 (0.66 to 9.6) contralateral tube 8 (3.7) 7 (3.0) 1.2 (0.45 to 3.4) persisting pregnancy of unknown location 3 (1.4) 2 (0.9) 1.6 (0.27 to 9.5) Ongoing pregnancy by: - OVIN no. (%) 0 3 (1.3) - - IUI no. (%) 0 1 (0.4) - - IVF no. (%) 7 (3.3) 2 (0.9) - a Cumulative ongoing pregnancy rate within time horizon of 36 months. b P value log rank test. 87

11 CHAPTER 5 The prespecified subgroup analyses indicated no beneficial significant effect on the cumulative ongoing pregnancy by natural conception in any of subgroups based on maternal age (<31.0 or 31.0 yr), history of a previous ectopic pregnancy (yes/no), pre-operative serum hcg concentration (<2,355 or 2,355 IU/L) or ectopic pregnancy size on ultrasound (<2.1 or 2.1 cm) (Table 4). The results of the analyses were similar irrespective whether the four women from the hospital which was unable to provide data were included or excluded. A meta-analysis, including our own data, confirmed that cumulative ongoing pregnancy rates by natural conception between salpingotomy and salpingectomy were comparable (figure 3). Meta-analysis of the outcome persistent trophoblast was not possible since only data from our study were available. The risk of repeat ectopic pregnancy was not statistically significant increased after salpingotomy (RR 1.2, 95% CI ). Cumulative ongoing pregnancy rate Number at risk Salpingotomy Salpingectomy Salpingotomy Salpingectomy Time after randomisation (months) Figure 2: Time to Ongoing Pregnancy by Natural Conception (Primary Outcome).* Life table analysis: Kaplan-Meier curves with 95% Confidence intervals. Median time to ongoing pregnancy by natural conception after salpingotomy 20 months (95% CI 17 to 23 months) and 26 months (95% CI 15 to 37) after salpingectomy; Log rank test P Value 0.678; Chi (df1). The cumulative ongoing pregnancy rate by natural conception was 60.7% after salpingotomy and 56.2% after salpingectomy. 88

12 FERTILITY AFTER SALPINGOTOMY AND SALPINGECTOMY Table 4. Ongoing Pregnancy by Natural Conception in Prespecified Subgroups. Subgroup a Salpingotomy Salpingectomy Age Women per subgroup no./total no. Women per subgroup no./total no. Fecundity Rate Ratio (95% CI) P Value for Interaction < 31.0 yr 57/105 55/ (0.80 to 1.7) yr 51/110 59/ (0.65 to 1.4) History of previous ectopic pregnancy Yes b 0/9 1/ No 108/ / (0.84 to 1.4) Pre-operative serum hcg < 2,335 IU/L 64/109 63/ (0.80 to 1.6) ,335 IU/L 43/103 48/ (0.65 to 1.5) Size Ectopic Mass on Ultrasound c < 2.1 cm 29/61 30/ (0.59 to 1.7) cm 34/64 27/ (0.82 to 2.3) a Continuous variables were dichotomized using medians. b No statistics are calculated because all cases are censored. c The size of the ectopic mass was registered in 254 of 293 women (86.7%) with an ectopic mass seen on ultrasound. 5 DISCUSSION In this randomised controlled trial we found that salpingotomy did not improve cumulative ongoing pregnancy rates by natural conception in women with a tubal pregnancy and a normal contralateral tube, but was associated with an increased risk of persistent trophoblast and a higher, though not statistically significant, repeat ectopic pregnancy rate. The hypothesis that women with tubal pregnancy and a normal contralateral tube might benefit from salpingotomy was based on the assumption that two tubes provide better pregnancy chances than a solitary tube. Our study rejects this hypothesis, as apparently only one properly functioning tube is equally sufficient for timely conception. This ESEP trial is the largest study to date that compares salpingotomy with salpingectomy in women with a normal contralateral tube. Recently, another randomised controlled trial (DEMETER) was published with a similar result on cumulative ongoing pregnancy rates (HR 1.13, 95% CI ) (14). A meta-analysis of both trials including 649 women showed no significant difference in cumulative ongoing pregnancy rates between salpingotomy and salpingectomy (panel, figure 3). Although statistical heterogeneity was not observed, we expect considerable clinical heterogeneity since there are differences between 89

13 CHAPTER 5 Study name Outcome Statistics for each study HR LL UL Z-value p-value Hazard ratio and 95% CI Mol 2013 Fernandez 2013 Fertility rate 1,060 0,806 1,394 0,417 0,676 1,130 0,732 1,745 0,552 0,581 1,079 0,856 1,361 0,647 0,518 0,01 0, Study name Outcome Statistics for each study RR LL UL Z-value p-value Risk ratio and 95% CI Mol 2013 PT 15,042 1, ,417 2,630 0,009 15,042 1, ,417 2,630 0,009 0,01 0, Study name Mol 2013 Outcome Repeat EP Statistics for each study RR LL UL Z-value p-value 1,612 0,795 1,324 1,324 0,185 Risk ratio and 95% CI Fernandez 2013 Repeat EP 0,647 0,188 2,222-0,692 0,489 1,287 0,697 2,375 0,806 0,420 0,01 0, Figure 3: Meta-analysis of the effect of studies comparing outcomes after salpingotomy and salpingectomy in women with tubal pregnancy. the populations studied, interventions and outcomes. In the ESEP study, women with contralateral tubal pathology were excluded as previous cohort studies indicated that these women might have a better fertility prognosis from conservative surgery, while these women were not excluded in the DEMETER study. The DEMETER study combined salpingotomy with a single shot systemic methotrexate, while our study performed salpingotomy alone (2,3,15). In the ESEP study, the primary outcome was of an ongoing pregnancy by natural conception, while in the DEMETER study a composite outcome including miscarriages and pregnancy terminations was used. In the DEMETER study, time to pregnancy was calculated from desire for pregnancy compared to time from randomisation in our study. We had considered a 15% difference in ongoing pregnancy rate as clinically relevant for the sample size calculation, in the ESEP trial, while the DEMETER study had used a 20% as a clinically relevant difference. A recent cohort study even demonstrated a difference of 10%, a difference that even was undetectable in our meta-analysis (16). In our opinion, it is unlikely that new randomized studies will have a power sufficient to draw definite conclusions on these rates. Our initial sample size calculation assumed that 276 women would have an ongoing pregnancy by natural conception. We discontinued the follow up of the study based on our judgment that further continuation was futile. At the time of discontinuation of the follow up in February 2013, 29 (6.5%) women were still in follow up. A sensitivity analysis showed no difference on the primary outcome measure under the assumption that these 29 women all achieved an ongoing pregnancy by natural conception. 90

14 FERTILITY AFTER SALPINGOTOMY AND SALPINGECTOMY For the outcome repeat ectopic pregnancy, both in the ESEP study and the DEMETER study, the numbers of repeat ectopic pregnancy were low. The point estimates were in opposite directions: we observed more repeat ectopic pregnancies after salpingotomy, whereas in the DEMETER study more repeat ectopic pregnancies were seen after salpingectomy. These effects were not statistically significant. In the meta-analysis, the summary point estimate for repeat ectopic pregnancy was in the direction of more repeat ectopic pregnancies after salpingotomy (I-square of 34%). Some aspects of our study warrant consideration. Women were randomised during surgery, and only postoperatively learned whether or not they were included in the trial and which intervention they received. The study, therefore, was not blinded for the patients. The researchers collecting data regarding fertility remained unaware of the treatment allocation. In doing so, we believe to have found a reasonable balance between our wish to inform women and safeguarding unbiased assessment of the primary outcome. The conversion rate from salpingotomy to salpingectomy during the initial surgery was 20%, similar to the DEMETER study. Limited data are available to compare this rate, which is otherwise prone to selection bias, for example by the size of the tubal pregnancy or the serum hcg level (17). This conversion rate increases the statistical uncertainty around the observed absence of effect, but the Per Protocol analysis -including only women who underwent the assigned intervention- showed similar point estimates and confidence intervals for the primary outcome measure. This confirms our findings of the intention to treat analysis and makes a positive effect of salpingotomy with a conversion rate of virtually zero unlikely. Our study was a pragmatic study which reflects current clinical practice. In future studies, the experience per surgeon, i.e. the number of previous interventions, should be registered, but it remains difficult which number to adhere to, to set a high quality standard of surgical skills. 5 Our results warrant the conclusion that salpingectomy is the preferred treatment in terms of efficacy. This conclusion is supported by the results of a previous patient preference study that showed a strong preference of women towards salpingectomy (18). Instead of future pregnancy prospects being the most important decisive factor, women preferred to reduce the risk of repeat ectopic pregnancy. Taking the data of the ESEP study and the metaanalysis into account, the surgical treatment of choice in women with a tubal pregnancy and a normal contralateral tube is salpingectomy. 91

15 CHAPTER 5 PANEL: RESEARCH IN CONTEXT System atic review We did an electronic search of the published medical literature (PubMed and Cochrane Controlled Trials Register) for studies in which women with tubal pregnancy were randomly allocated to treatment with salpingotomy or salpingectomy with the intention to assess future fertility. We used the search terms ectopic pregnancy AND randomized controlled trial. We considered all published randomised controlled trials in which salpingotomy was compared with salpingectomy in women with tubal pregnancy to assess fertility. Two reviewers (FM and PJH) reviewed identified papers for relevance and quality, and abstracted the data. Published studies were assessed for quality according to with the Cochrane Collaboration s tool for assessing risk of bias (19). Our primary outcomes were time to the subsequent ongoing pregnancy by natural conception, the occurrence of persistent trophoblast and the occurrence of repeat ectopic pregnancy. We calculated Hazard Ratios (HR) for the outcome time to subsequent ongoing pregnancy by natural conception and Risk Ratios (RR) with 95% CIs for the primary outcomes persistent trophoblast and repeat ectopic pregnancy. Searching of published work yielded one result relevant for meta-analysis.14 Review of the paper indicated that it fulfilled the inclusion criteria for assessing risk of bias. Interpretation Findings from this meta-analysis, which included the results of our trial, showed that in women with a tubal pregnancy, salpingotomy does not improve fertility prospects over salpingectomy. Additional members of ESEP study group In addition to the authors, the following ESEP study group members participated in the study: AB Dijkman, M.D. (Boven IJ Hospital, Amsterdam), AL Thurkow, M.D. (St. Lucas/Andreas Hospital, Amsterdam), HJHM van Dessel, M.D., Ph.D. (Twee Steden Hospital, Tilburg), PJQ van der Linden, M.D., Ph.D. (Deventer Hospital, Deventer), FW Bouwmeester, M.D. (Waterland Hospital, Purmerend), GJE Oosterhuis, M.D., Ph.D. (Medical Spectrum Twente, Enschede), JJ van Beek, M.D., Ph.D. (VieCuri Medical Centre, Venlo), MH Emanuel, M.D., Ph.D. (Spaarne Hospital, Hoofddorp), H Visser, M.D. (Ter Gooi Hospital, Blaricum), JPR Doornbos, M.D., Ph.D. (Zaans Medical Centre, Zaandam), PJM Pernet, M.D. (Kennemer Gasthuis, Haarlem), J Friederich, M.D. (Gemini Hospital, Den Helder) all in The Netherlands; F Pettersson M.D., Ph.D. (Kvinnokliniken, Länssjukhuset, Halmstad), Z Sabetirad M.D. (Kvinnokliniken, Centralsjukhuset, Karlstad), K Nilsson M.D., Ph.D. (Kvinnokliniken, Universitetssjukhuset Örebro), G Tegerstedt M.D., Ph.D. (Kvinnokliniken, Södersjukhuset, Stockholm), JJ Platz- Christensen, M.D., Ph.D. (Norra Älvsborgs Läns Sjukhus, Trollhättan) all in Sweden. 92

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