Fertility after tubal ectopic pregnancy: results of a population-based study

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1 Fertility after tubal ectopic pregnancy: results of a population-based study Marianne de Bennetot, M.D., a Benoît Rabischong, M.D., Ph.D., a Bruno Aublet-Cuvelier, M.D., Ph.D., b Fabien Belard, b Herve Fernandez, M.D., c Jean Bouyer, M.D., Ph.D., d Michel Canis, M.D., Ph.D., a and Jean-Luc Pouly, M.D. a a Department of Obstetrics and Gynecology, P^ole de Gynecologie-Obstetrique, Centre Hospitalier Universitaire Estaing, Clermont-Ferrand; b Department of Medical Information, Centre Hospitalier Universitaire Gabriel Montpied, Clermont- Ferrand; c Department of Obstetrics and Gynecology, H^opital Bic^etre, Le Kremlin Bic^etre; and d Centre de Recherche en Epidemiologie et Sante des Populations UMRS 1018 Inserm, UPS11, Ined. Equipe Reproduction et Developpement de l Enfant, CESP-INSERM U1018, Le Kremlin Bic^etre, France Objective: To assess the reproductive outcome after an ectopic pregnancy (EP) based on the type of treatment used, and to identify predictive factors of spontaneous fertility. Design: Observational population based-study. Setting: Regional sistry. Patient(s): One thousand sixty-four women registered from 1992 to Intervention(s): Laparoscopic (radical or conservative), or medical treatment. Main Outcome Measure(s): Epidemiologic characteristics, clinical presentation, treatments performed, reproductive outcome, recurrence. Result(s): The 24-month cumulative rate of intrauterine pregnancy (IUP) was 67% after salpingectomy, 76% after salpingostomy, and 76% after medical treatment. IUP rate was lower after radical treatment compared with conservative treatments in univariable analysis. In multivariate analysis, IUP rate was significantly lower for patients >35 years old or with history of infertility or tubal disease. For them, IUP rate was significantly higher after conservative treatment compared with salpingectomy. The 2-year cumulative rate of recurrences was 18.5% after salpingostomy or salpingectomy and 25.5% after medical treatment. History of infertility or of previous live birth would be protective, in contrast to history of voluntary termination of pregnancy. Conclusion(s): Conservative strategy seems to be preferred, whenever possible, to preserve patients fertility without increasing the risk of recurrence. The choice between conservative treatments does not rely on subsequent fertility, but more likely on their own indications and therapeutic effectiveness. Risk factors of recurrence could be considered for secondary prevention. (Fertil Steril Ò 2012;98: Ó2012 by American Society for Reproductive Medicine.) Key Words: Fertility, ectopic pregnancy, recurrence, risk factor, treatment method, laparoscopy, methotrexate Discuss: You can discuss this article with its authors and with other ASRM members at fertstertforum.com/debennetotm-fertility-tubal-ectopic-pregnancy-population-based-study/ Use your smartphone to scan this QR code and connect to the discussion forum for this article now.* * Download a free QR code scanner by searching for QR scanner in your smartphone s app store or app marketplace. Ectopic pregnancies (EPs) occur among 2% of pregnant women in developed countries (1) and may seriously compromise women s health and future fertility (2). The management of EPs has made significant progress in diagnostic and therapeutic efficiency (3, 4). Over the past 40 years, laparoscopy has emerged as the criterion standard technique for the surgical management of EP (5), and in the meantime medical treatment with Received April 11, 2012; revised June 12, 2012; accepted June 14, 2012; published online July 18, M.d.B. has nothing to disclose. B.R. has nothing to disclose. B.A.-C. has nothing to disclose. F.B. has nothing to disclose. H.F. has nothing to disclose. J.B. has nothing to disclose. M.C. has nothing to disclose. J.-L.P. has nothing to disclose. Reprint requests: Benoît Rabischong, M.D., Ph.D., 1, Place Lucie Aubrac, Clermont-Ferrand, France ( brabischong@chu-clermontferrand.fr). Fertility and Sterility Vol. 98, No. 5, November /$36.00 Copyright 2012 American Society for Reproductive Medicine, Published by Elsevier Inc. methotrexate has been widely developed (5, 6). Whatever the treatment, in addition to its effectiveness, the current issue is the preservation of patients fertility, including limiting the risk of recurrence. The role of treatment in optimizing subsequent fertility is a controversial subject, which has not been settled by previous studies (7). Fertility after laparoscopic salpingectomy has been compared with laparoscopic salpingostomy in many retrospective studies or reviews. Some VOL. 98 NO. 5 / NOVEMBER

2 ORIGINAL ARTICLE: INFERTILITY didn t seem to show a difference between the two techniques (8 10), whereas others showed higher rates of intrauterine pregnancy (IUP) after conservative-surgical treatment (11 13). However, the results of these studies were not statistically significant after adjustment for confounders. Similarly, the risk of recurrence according to the surgical techniques is still discussed, with some retrospective studies showing higher recurrence rates after laparoscopic salpingostomy (11), and others no difference (8, 13, 14). More recently, the question arose of the existence of a variation of future fertility based on the conservative treatment chosen: laparoscopic salpingostomy or medical treatment with methotrexate. Few prospective randomized studies have been published, and their results do not support a conclusion on this issue (15, 16). The present study aimed to compare the subsequent fertility of women who had experienced EP according to the type of treatment they received radical, conservative-surgical or medical and to find risk factors of repeated ectopic pregnancy. It was based on population-based data of the Auvergne (France) Ectopic Pregnancy Registry. METHODS The Auvergne Ectopic Pregnancy Registry data were analyzed from 1992 to The methodology of the registry has been described previously (1, 17). All of the women from 15 to 44 years old, who resided permanently in the Auvergne region, treated for an EP in one of the 20 health center areas were registered. They were prospectively followed until the age of 45 years to study their reproductive outcome. The information collected for each woman included: sociodemographic characteristics; sexual, gynecologic, reproductive, and surgical histories; smoking habits; condition of conception (e.g., contraception, ovulation induction); results of Chlamydia trachomatis serologic tests; characteristics of the EP; and treatment procedures used. Women followed were interviewed on the phone every 6 months during the first 2 years and every year after. The questions focused on the quest for a new pregnancy, getting pregnant again, the outcome of subsequent pregnancies, and the use of contraceptives and medical measures related to infertility. To evaluate the accuracy of the registry, the discharge diagnosis files of the different centers from 1993 onward were reviewed (two-source capture-recapture method). The completeness of the register was estimated to be 90%. The registry was granted and qualified by Comite National des Registres (CNR). Data collected were treated confidentially according to Commision Nationale de l Informatique et Liberte (CNIL) statements. Institutional Review Board approvals from CNR and CNIL were obtained. Data were then centralized at the Department of Medical Information of the Centre Hospitalier Universitaire in Clermont-Ferrand. After excluding patients with prior history of an EP, patients who did not report seeking pregnancy during followup, those who benefited from a second-line treatment, those treated with RU-486 or laparotomy, and patients supported with in vitro fertilization (IVF), 1,622 patients met our inclusion criteria. Among them, 558 patients were not retained in the study because they were lost in follow-up (n ¼ 314; 12.3%) or because they were 45 years old or were minor or received bilateral salpingectomy with no desire of IVF. Finally, reproductive outcome were studied for 1,064 patients (Supplemental Fig. 1, available online at Patients received conservative medical, conservative laparoscopic, or radical laparoscopic treatment. Medical treatment was chosen for asymptomatic patients with no evidence of tubal rupture and b-hcg <5,000 UI/L. The protocol consisted of an intramuscular injection of a single dose of methotrexate (50 mg/m 2 ). In case of history of methotrexate failure, surgical treatment was chosen. The decision between salpingostomy and salpingectomy was based on the pretherapeutic score proposed by Pouly et al. (18). All IUPs were taken into account regardless of the outcome. For fertility study, if a recurrence occurred, it was ignored and the follow-up continued, and conversely for the recurrence study. Only the first IUP or the first recurrence was registered. In both cases, survival analysis methods were used, with a calculation of the time needed to conceive, which is the cumulative period of time during which a woman is trying to become pregnant until she gets pregnant or is censored. Because only spontaneous fertility was studied, the follow-up was censored if a woman began an IVF program. For subsequent spontaneous IUP, we first analyzed the whole sample. According to the results of our previous studies, women with history of infertility or tubal disease at the time of the first EP and those >35 years old were studied separately from the others (19). The group of patients with a history of tubal disease included women who, at the time of inclusion in the register, said that they have had a history of tubal surgery or microsurgery, pelvic inflammatory disease, and/or Chlamydia trachomatis infection. Cumulative rates of recurrent EP and spontaneous IUP were calculated by the Kaplan-Meier estimator with confidence interval for each of the three treatments. The curves obtained were compared by log rank tests for single-variable analysis and by Cox regression to take into account confounding variables, such as sociodemographic and clinical characteristics of women, that may influence the choice of treatment. Regarding recurrences, risk factors were also searched by single-variable and multivariable analysis. Statistical analysis was performed with the use of SAS statistical software v8.02 (SAS Institute). Statistical significance was established at P<.05. RESULTS Fertility Outcome The treatment given was radical for 299 women (28%), conservative-surgical for 646 (61%), and conservativemedical for 119 (11%). Some sociodemographic and clinical characteristics of the women differed according to the treatment they had received (Supplemental Table 1). Among the 1,064 women who attempted to conceive again, 744 were pregnant spontaneously. The outcome of these pregnancies was 82% for a vaginal delivery or cesarean section, 17% for miscarriage, and 1% for a voluntary 1272 VOL. 98 NO. 5 / NOVEMBER 2012

3 Fertility and Sterility FIGURE 1 Cumulative rates of spontaneous intrauterine pregnancy (Kaplan-Meier method). termination of pregnancy. Pregnancy outcome was independent from the treatment of EP (P¼.97). The 24-month cumulative rate of spontaneous IUP was 67% (95% CI ) for radical treatment, 76% (95% CI ) for conservative-surgical treatment, and 76% (95% CI ) for conservative-medical treatment (Fig. 1). The crude cumulative rates of IUP were different according to the treatment methods in univariable analysis (P¼.0079), with a lower fertility after radical treatment (Table 1) compared with conservative treatments. In multivariate analysis, there was no significant difference between the three treatments (Table 1). We reached the same finding when we compared fertility after radical treatment and after conservative treatment, all surgical and medical ones taken into account (hazard ratio [HR] 0.86, 95% CI ). The characteristics of these women seemed to influence reproductive performance significantly. Thus, the rate of IUP was significantly lower for women aged >35 years (HR 0.50, 95% CI ) or with history of infertility (HR 0.51, 95% CI ) or of tubal disease (HR 0.62, 95% CI ). Conversely, subsequent fertility was better in case of history of live birth (HR 1.20, 95% CI ) or in case of EP with intrauterine device (IUD; HR 2, 95% CI ; Table 1). Multivariable analysis was also made on the subgroup of women with a history of infertility, tubal disease, or age R35 years (n ¼ 430) (subgroup 1). In this subgroup, patients treated by conservative medical or surgical treatment had significantly more IUP compared with patients treated radically (HR 0.67, 95% CI ; Table 2). For patients of this first subgroup, the fertility rate was significantly higher for women with history of live birth (HR 1.52, 95% CI ) and, for the two subgroups, in case of EP with IUD (HR 3.60, 95% CI ; and HR 1.78, 95% CI ). In the second subgroup that included women <35 years old with no infertility history or tubal disease (n ¼ 634), the difference in subsequent fertility between the three treatments was not significant (HR 0.99, 95% CI ). Recurrences Among the 1,064 women studied, 111 had a recurrence of EP (10.5%). The 2-year cumulative rate of recurrence was 19% TABLE 1 Univariate and multivariate analysis of factors influencing fertility. Adjusted hazard ratio b 95% CI n a Univariate analysis Treatment Radical Conservative-surgical Conservative-medical History of infertility History of live birth History of miscarriage History of abortion Tubal disease EP with IUD Age, y < R Smoking habits University studies Results of multivariate analysis, Cox model Treatment Radical Conservative-surgical 1 Conservative-medical Age, y < R History of infertility History of live birth Tubal disease EP with IUD Note: EP ¼ ectopic pregnancy; IUD ¼ intrauterine device; CI ¼ confidence interval. a Number of patients for whom time to conceive was known. b Adjusting for all variables in the table as well as the size of the EP treatment center. VOL. 98 NO. 5 / NOVEMBER

4 ORIGINAL ARTICLE: INFERTILITY TABLE 2 Multivariable analysis of the two subgroups of women depending on history of infertility, tubal disease, or age at the time of EP. Adjusted hazard ratio a 95% CI Subgroup 1: women with a history of infertility or tubal disease or aged R35 y Treatment Radical Conservative-surgical 1 Medical History of live birth EP with IUD Subgroup 2: women aged <35 y, with no infertility history or tubal disease Treatment Radical Conservative-surgical 1 Medical History of live birth EP with IUD Note: EP ¼ ectopic pregnancy; IUD ¼ intrauterine device; CI ¼ confidence interval. a Adjusting for all variables in the table as well as the size of the treatment center of EP. whatever the treatment received. There was 18.5% recurrence after salpingostomy or salpingectomy and 25.5% after medical treatment. The rate of repeated EP was not significantly different according to the treatment (P¼.86; Fig. 2). The same result was obtained for patients in the subgroups 1 and 2 taken separately. After adjustment to confounders, the rate of recurrence was significantly higher among women who had a history of voluntary termination of pregnancy (HR 1.8, 95% CI ). Conversely, fewer recurrences occurred among women having a history of infertility (HR 0.5, 95% CI ) or previous live birth (HR 0.6, 95% CI ) (Supplemental Table 2, available online at FIGURE 2 Cumulative rates of repeated ectopic pregnancy depending on the treatment. DISCUSSION Beyond the development of less invasive treatment, fertility in the wake of an ectopic pregnancy remains a major issue. As such, the present study is an interesting source of data, because it was conducted in the general population, with 90% of the patients treated for EP during 17 years in the Auvergne region. Few women (12.3%) could not be followed. All of the women were followed prospectively and interviewed regularly after EP, so the real fertility outcomes were known without biases, taking into account whether the woman was trying to become pregnant again. Thus, selection and recall biases, which frequently occur in retrospective studies with hospital recruitment, were avoided. But, owing to the lack of randomization, our results can be weighted because of the inevitable existence of confounding factors in the choice of treatment of EP and because the indication of each type of therapy could be different, introducing a possible bias. Indeed, the therapeutic strategy explained in the Methods may have been influenced by sociodemographic or patient history. Figure 1 represents, by the Kaplan-Meier method, the cumulative IUP rate as a function of time. The curves representing fertility after conservative treatments are quite distinct from that showing fertility after salpingectomy. Not taking into account confounding factors, this figure may illustrate the results of the univariate analysis. Our results effectively show a significant difference in terms of fertility between conservative and radical treatments in univariable analysis, with higher rates of IUP after conservative techniques. These results are really interesting to be observed, but they may be influenced by the fact that they ignored confounding factors. Thus, according to multivariable analysis, there is no statistically significant difference between the three treatments. Regarding surgical treatment, many retrospective studies compared subsequent fertility after laparoscopic salpingectomy versus salpingostomy. According to some studies, there was no statistical difference in subsequent fertility depending on the treatment (8, 9). However the trend in favor of conservative treatment was already observed by some retrospective studies (12, 13) and reviews (11). Regarding conservative treatments, our results do not show any difference for subsequent fertility in terms of IUP rate, between medical or surgical treatment. These results were observed in patients whether they had risk factors of infertility or not. The value of these results may be limited due to the lower proportion of medically treated patients in our study. Yet, a recent review showed the same findings (20). Similarly, the randomized trial by Hajenius et al. (21) that compared fertility after conservative-medical treatment with multiple doses of methotrexate versus conservativesurgical treatment showed no difference in the rate of IUP. Otherwise, after adjustment to confounders, history of infertility, tubal disease, and being >35 years old appear to be pejorative factors for fertility with significantly lower rates of IUP after EP, as already shown by Ego et al. (22). That s why we chose to study the pregnancy rate of those patients particularly according to the treatment. Thus, considering only women with these risk factors, there were significantly higher rates of IUP after conservative treatments in multivariable analysis. This result is of importance, because the optimization of fertility for those patients is especially more 1274 VOL. 98 NO. 5 / NOVEMBER 2012

5 Fertility and Sterility sensitive. Recently, the prospective study by Becker et al. (23) of 261 patients also showed that laparoscopic salpingostomy is of particular benefit for patients with additional fertilityreducing factors if desirous of a future pregnancy. The prospective randomized trials currently underway, DEMETER in France and METEX and ESEP in The Netherlands and Scandinavia, are likely to bring other elements to this discussion (24, 25). Regarding recurrences, published studies and conclusions are divided. Some found a higher risk of recurrence after laparoscopic salpingostomy (11). For others the rate of recurrence was similar after salpingectomy and salpingostomy (13, 26, 27). On this point, results of the present study are particularly interesting because there is no difference whatever the treatment received. Indeed, in aggregate or in subgroups depending on their history, patients had no more recurrence after radical-surgical, conservative-surgical, or conservative-medical treatments. Therefore, the risk of recurrence should not be an argument for salpingectomy. Furthermore, results show that patients with history of live birth or of infertility had significantly lower rates of recurrence. The protective effect of multiparity was already suggested by Tuomivaara and Kauppila (26). The lower rate of recurrence in case of history of infertility could be explained by an overall decline in fertility for these patients. Conversely, women with history of voluntary termination of pregnancy had significantly higher rates of second EP. This result is to be taken with caution, because of the heterogeneity of the abortion rate between regions. However, these results could have an interest for secondary prevention, to better identify patients at risk of recurrence and strengthen the promotion of appropriate contraception or close monitoring in early pregnancy. Taking into account our results, the preservation of fertility doesn t seem to be an argument that should guide the choice between methotrexate and laparoscopic salpingostomy. Each of these treatments, especially medical treatment, has its own indications based on different arguments such as the existence of clinical symptoms and signs of tubal rupture or the rate of b-hcg. The therapeutic strategy must consider the effectiveness of treatments, especially because reported failure rates of the two treatments are not similar in the general population. Recent results from the Auvergne registry showed an average failure rate of 6.6% for salpingostomy with a standardized surgical technique (28) and 24.6% after a single dose of methotrexate with an increased risk of failure (16.5% vs. 40%) if the rate of initial b-hcg is >1,300 UI (29). In conclusion, the results of this study and literature data show that it seems preferable, whenever it is possible, to always opt for a conservative treatment to potentiate subsequent fertility while not increasing the risk of recurrence. Indeed, there are better fertility rates after conservative strategy, especially for patients with a risk factor of infertility. Moreover there is no more risk of recurrence after salpingostomy or methotrexate therapy than after salpingectomy. Beyond the therapeutic indications, the choice between two conservative treatments should be based on other parameters, such as therapy effectiveness, and perhaps quality of life, a parameter that might be interesting to study in the future. REFERENCES 1. Coste J, Job-Spira N, Aublet-Cuvelier B, Germain E, Glowaczower E, Fernandez H, Pouly JL. Incidence of ectopic pregnancy. First results of a population-based register in France. Hum Reprod 1994;9: Walker JJ. Ectopic pregnancy. Clin Obstet Gynecol 2007;50: Bruhat MA, Manhes H, Mage G, Pouly JL. Treatment of ectopic pregnancy by means of laparoscopy. Fertil Steril 1980;33: Tanaka T, Hayashi H, Kutsuzawa T, Fujimoto S, Ichinoe K. Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case. Fertil Steril 1982;37: Hajenius PJ, Mol F, Mol BW, Bossuyt PM, Ankum WM, van der Veen F. Interventions for tubal ectopic pregnancy. 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6 ORIGINAL ARTICLE: INFERTILITY 25. Mol F, Strandell A, Jurkovic D, Yalcinkaya T, Verhoeve HR, Koks CA, et al. The ESEP study: salpingostomy versus salpingectomy for tubal ectopic pregnancy; the impact on future fertility: a randomised controlled trial. BMC Womens Health 2008;8: Tuomivaara L, Kauppila A. Radical or conservative surgery for ectopic pregnancy? A follow-up study of fertility of 323 patients. Fertil Steril 1988;50: Kuroda K, Takeuchi H, Kitade M, Kikuchi I, Shimanuki H, Kumakiri J, et al. Assessment of tubal disorder as a risk factor for repeated ectopic pregnancy after laparoscopic surgery for tubal pregnancy. J Obstet Gynaecol Res 2009; 35: Rabischong B, Larraín D, Pouly J-L, Jaffeux P, Aublet-Cuvelier B, Fernandez H. Predicting success of laparoscopic salpingostomy for ectopic pregnancy. Obstet Gynecol 2010;116: Rabischong B, Tran X, Sleiman AA, Larraín D, Jaffeux P, Aublet-Cuvelier B, et al. Predictive factors of failure in management of ectopic pregnancy with single-dose methotrexate: a general population-based analysis from the Auvergne Register, France. Fertil Steril 2011;95: VOL. 98 NO. 5 / NOVEMBER 2012

7 Fertility and Sterility SUPPLEMENTAL FIGURE 1 Schema of inclusion of patients. EP ¼ ectopic pregnancy. VOL. 98 NO. 5 / NOVEMBER e1

8 ORIGINAL ARTICLE: INFERTILITY SUPPLEMENTAL TABLE 1 Characteristics of 1,064 women by first-line treatment of index EP. Radical (n [ 299) a First-line treatment Conservative-surgical Conservative-medical (n [ 646) a (n [ 119) a % 95% CI % 95% CI % 95% CI P value b Distribution of treatments Sociodemographic characteristics University educated Not of French origin Age at inclusion, y <.001 < R Smoking habits Center treating >20 EP/y <.001 Clinical characteristics History of infertility Previous spontaneous abortion Previous induced abortion History of live birth <.001 Tubal disease <.001 EP with IUD Normal controlateral tube Note: EP ¼ ectopic pregnancy; IUD ¼ intrauterine device; CI ¼ confidence interval. a The numbers may be different depending on the variables because of missing data. b P values for c 2 tests e2 VOL. 98 NO. 5 / NOVEMBER 2012

9 Fertility and Sterility SUPPLEMENTAL TABLE 2 Multivariable analysis of factors influencing the risk of ectopic pregnancy recurrence (Cox model). Adjusted hazard Variable ratio 95% CI History of infertility History of live birth History of abortion Note: CI ¼ confidence interval. VOL. 98 NO. 5 / NOVEMBER e3