If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
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.
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.
). 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 (
). Fertility after laparoscopic salpingectomy has been compared with laparoscopic salpingostomy in many retrospective studies or reviews. Some didn’t seem to show a difference between the two techniques (
). 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 (
). 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 (
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.
The Auvergne Ectopic Pregnancy Registry data were analyzed from 1992 to 2008. The methodology of the registry has been described previously (
). 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 Comité National des Registres (CNR). Data collected were treated confidentially according to Commision Nationale de l’Informatique et Liberté (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 follow-up, 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 = 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 www.fertstert.org).
Patients received conservative medical, conservative laparoscopic, or radical laparoscopic treatment. Medical treatment was chosen for asymptomatic patients with no evidence of tubal rupture and β-hCG <5,000 UI/L. The protocol consisted of an intramuscular injection of a single dose of methotrexate (50 mg/m2). 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. (
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 (
). 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.
The treatment given was radical for 299 women (28%), conservative-surgical for 646 (61%), and conservative-medical 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 termination of pregnancy. Pregnancy outcome was independent from the treatment of EP (P=.97).
The 24-month cumulative rate of spontaneous IUP was 67% (95% CI 0.61–0.74) for radical treatment, 76% (95% CI 0.73–0.8) for conservative-surgical treatment, and 76% (95% CI 0.65–0.85) for conservative-medical treatment (Fig. 1).
The crude cumulative rates of IUP were different according to the treatment methods in univariable analysis (P=.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 0.72–1.02).
Table 1Univariate and multivariate analysis of factors influencing fertility.
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 0.37–0.67) or with history of infertility (HR 0.51, 95% CI 0.40–0.64) or of tubal disease (HR 0.62, 95% CI 0.50–0.77). Conversely, subsequent fertility was better in case of history of live birth (HR 1.20, 95% CI 1.01–1.42) or in case of EP with intrauterine device (IUD; HR 2, 95% CI 1.56–2.55; Table 1).
Multivariable analysis was also made on the subgroup of women with a history of infertility, tubal disease, or age ≥35 years (n = 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 0.50–0.91; 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 1.14–2.02) and, for the two subgroups, in case of EP with IUD (HR 3.60, 95% CI 2.18–5.97; and HR 1.78, 95% CI 1.34–2.37). In the second subgroup that included women <35 years old with no infertility history or tubal disease (n = 634), the difference in subsequent fertility between the three treatments was not significant (HR 0.99, 95% CI 0.80–1.23).
Table 2Multivariable analysis of the two subgroups of women depending on history of infertility, tubal disease, or age at the time of EP.
Among the 1,064 women studied, 111 had a recurrence of EP (10.5%). The 2-year cumulative rate of recurrence was 19% 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 (P=.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 1.1–3.0). Conversely, fewer recurrences occurred among women having a history of infertility (HR 0.5, 95% CI 0.3–0.8) or previous live birth (HR 0.6, 95% CI 0.4–0.9) (Supplemental Table 2, available online at www.fertstert.org).
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 (
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 (
) that compared fertility after conservative-medical treatment with multiple doses of methotrexate versus conservative-surgical 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. (
). 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 sensitive. Recently, the prospective study by Becker et al. (
) of 261 patients also showed that laparoscopic salpingostomy is of particular benefit for patients with additional fertility-reducing 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 (
). 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 (
). 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 β-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 (
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.
Supplemental Table 1Characteristics of 1,064 women by first-line treatment of index EP.
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.
Ectopic pregnancy occurs in 1%–2% of pregnancies, and despite vast improvements in our diagnostic capability, it continues to be the leading cause of pregnancy-related death in the first trimester. Currently, ectopic pregnancy can be diagnosed accurately using ultrasound imaging in conjunction with beta hCG measurements. Treatment options include expectant management, medical therapy with methotrexate (MTX), and either surgical salpingostomy or salpingectomy. Our understanding of the long-term effects of these treatment options on fertility is confounded not only by the complexity of the causes of ectopic pregnancy, and therefore risk for recurrence or infertility, but also by the lack of research unbiased by physician preference.