OBJECTIVE: To estimate predictive factors for failure of laparoscopic conservative treatment of ectopic pregnancy using a standardized surgical technique.
METHODS: We performed a population-based study from the Auvergne ectopic pregnancy registry. A total of 3,196 cases of ectopic pregnancy were registered between 1992 and 2008. Among conservative treatments (n=1,965), 1,306 (66.5%) patients underwent laparoscopic salpingostomy exclusively. For each case, collected data included: sociodemographic characteristics, previous surgeries, gynecologic and reproductive histories, conditions of conception, Chlamydiae trachomatis serology, human chorionic gonadotropin (hCG) levels, and ectopic pregnancy characteristics. Univariable and multivariable analyses were performed to identify risk factors for treatment. A receiver operating characteristic curve was also provided. Statistical significance was established at P<.05.
RESULTS: We identified 86 treatment failures (6.6%). The failure rate remained stable through the study period. Pretherapeutic hCG level was the only factor significantly associated with treatment failure. Patients with an hCG level of at least 1,960 international units/L had a failure rate of 8.6% compared with 5.1% in patients with a lower hCG level (P=.03). Sensitivity and specificity of this cutoff limit were 47% and 67%, respectively (likelihood ratio(+)=1.4 and likelihood ratio(−)=0.8).
CONCLUSION: The hCG level of at least 1,960 international units/L is the only factor related to treatment failure. However, the prognostic value of this cutoff is low and with limited clinical relevance.
LEVEL OF EVIDENCE: II
In the general population, a higher failure rate after laparoscopic salpingostomy can be expected in patients with human chorionic gonadotropin levels of at least 1,960 international units/L.
From the Departments of Gynecology–Obstetrics and Human Reproduction and Medical Information, CHU Estaing, Clermont-Ferrand, France; and the Department of Obstetrics and Gynecology, Pôle Bicêtre-Béclère, Université Paris 11, Le Kremlin-Bicêtre Cedex, France.
Corresponding author: Benoit Rabischong, MD, 1, Place Lucie Aubrac, 63003, Clermont-Ferrand Cedex 1, France; e-mail: email@example.com.
Financial Disclosure The authors did not report any potential conflicts of interest.
Ectopic pregnancy occurs in approximately 1–2% of pregnant women and may seriously compromise women's health and future fertility.1 Historically, women with ectopic pregnancy typically presented with the triad of delayed menses, pain, and abnormal bleeding and were treated by laparotomy and salpingectomy. Today, sensitive human chorionic gonadotropin (hCG) assays and transvaginal ultrasonography can lead to earlier diagnosis, allowing conservative surgical treatment with preservation of the tube.2
Since the late 1970s,3–5 several studies had demonstrated the advantages of laparoscopy over laparotomy in terms of postoperative recovery and costs,6–11 turning laparoscopy into the gold standard technique in the surgical management of ectopic pregnancy.12
Laparoscopic surgery may be conservative (salpingostomy) or radical (salpingectomy).1 To date, no randomized trials have specifically compared both techniques, but some studies have demonstrated that salpingostomy is more cost-effective13 and may result in improved fertility rates.14–16 However, a well-recognized hazard of conservative treatment is incomplete removal of trophoblastic tissue, resulting in rising or plateauing serum hCG concentrations postoperatively (persistent trophoblast). This, so-called “persistent ectopic pregnancy” may proliferate and cause clinical symptoms and morbidity requiring further treatments.17–19
The objective of this study is to elucidate factors that influence the failure or success of laparoscopic conservative treatment of ectopic pregnancy in a general population using a standardized surgical technique.
MATERIALS AND METHODS
The Auvergne Ectopic Pregnancy Register was initiated in 1992 on a general population basis, including actually three departments of Auvergne's region (France): Allier, Cantal, and Puy-de-Dôme. The methodology of Auvergne's register has been previously described.20 Twenty notification medical centers, public and private, participated in the construction of the database by registering prospectively all their new cases of ectopic pregnancy since 1992.
All women aged 15–45 years who resided permanently in Auvergne's region who were treated for ectopic pregnancy in any of the 20 medical establishments enrolled were included and prospectively followed until the age of 45 years to study their reproductive outcome.
In each center, a trained investigator was in charge of case identification, follow-up, and data collection based on a preestablished questionnaire. Data collected included: sociodemographic characteristics; sexual, gynecological, reproductive and surgical histories; smoking habits; conditions of conception (eg, contraception, ovulation induction); results of Chlamydiae trachomatis serology; and hCG levels. Data concerning ectopic pregnancy characteristics (eg, site, tubal rupture, hemoperitoneum) and the treatments performed were also collected. For case follow-up, women were interviewed by phone every 6 months during the first 2 years and every year after about their desire or not for a new pregnancy, achievement or not of pregnancy, time to pregnancy or time at risk of pregnancy, use of contraceptives and medical measures related to infertility, and obstetric outcome (if pregnancy occurred).
To evaluate the accuracy of the register, the discharge diagnosis files of the different centers from 1993 onward were reviewed and a two-source capture–recapture study was performed.21 This method examines the degree of overlap between two (or more) data sources and estimates the total population size and the number of missed cases by each source by means of a formula.22
Overall the register completeness remained stable during all the study period, reflecting the quality of the information described with an estimated exhaustiveness ratio of 90%. The information collected was treated confidentially according to professional secrecy and Commision National de l‘Informatique et Liberté statements. The register was qualified by Comité National des Registres. Data were then centralized at Department of Medical Information of Clermont-Ferrand's CHU. Institutional Review Board approvals from Comité National des Registres and Commision National de l‘Informatique et Liberté were obtained.
Between January 1992 and December 2008, 3,196 cases of ectopic pregnancy were registered. Among these patients, 1,216 (38%) underwent radical treatment. Conservative management, either medical or surgical, was performed in 1,965 (61.5%) women. Fifteen patients (0.5%) were excluded from the analysis because of missing data.
From the 1,965 patients managed conservatively, 1,447 (73.6%) underwent surgical management and 518 (26.4%) medical treatment. Among patients who underwent salpingostomy, 1,306 (66.5%) were treated exclusively by laparoscopy and 141 (7.2%) received also medical therapy as primary treatment (Fig. 1).
The presented analysis was based on the 1,306 patients who underwent exclusive conservative laparoscopic treatment.
Our management protocol did not change during the study period. The decision between salpingostomy or salpingectomy was based on the pretherapeutic score proposed by Pouly et al23 in 1991 before the creation of the register.
Our technique and instrumentation for laparoscopic salpingostomy were based on the same principles described by Bruhat et al3–5 in late 1970s. In all cases, a 10- to 15-mm linear salpingotomy was performed with a fine monopolar diathermy needle along the antimesenteric tubal border overlying the ectopic pregnancy at the point of its maximal bulge. A 10-mm gauge aspiration cannula was inserted through the incision for removing the trophoblastic tissue by combining aspiration and irrigation. When required, extraction of the ectopic pregnancy was completed using fine blunt forceps. Salpingostomy was left open to heal by secondary intention.
We defined failure as rising or plateauing postoperative serum hCG levels that required additional medical or surgical treatment after initial removal of the ectopic pregnancy by laparoscopic salpingostomy.
Based on postoperative outcome, the 1,306 cases were divided into two groups: cases managed successfully and cases that required further treatment for persistent ectopic pregnancy (failures). To identify risk factors for failure, the two groups were compared by univariable analysis using χ2 or Fisher's exact test when appropriate with odds ratio (OR) (95% confidence interval [CI]). If risk factors of failure were found in univariable analysis, variables presumed to have clinical significance (P<.20) then were subjected to multivariable logistic regression analysis to confirm their significance using the SAS System 8.02. The level of statistical significance was established at P<.05. Qualitative data are expressed in percentage (95% CI) and quantitative data are expressed as the mean±standard deviation.
The receiver operating characteristic curve was used to determine the optimum discriminatory level of preoperative hCG serum titers.
For the 1,306 cases of ectopic pregnancy managed exclusively by means of laparoscopic conservative surgery, the mean rate of preoperative serum hCG titer was 2,953.3±7,061.7 international units/L (95% CI 2,558.6–3,348 international units/L).
Among these patients, 1,220 (93.4% [92.1–94.8]) were successfully treated and 86 (6.6% [5.2–7.9]) cases required further treatment for persistent ectopic pregnancy (failures). The mean hCG level was not different between patients treated successfully and failures, 2,900.5±7,156.1 international units/L (2,487.4–3,313.6 international units/L) compared with 3,745.7±5,428.6 international units/L (2,513.6–4,977.9 international units/L), respectively (P=.20, nonsignificant). The failure rate remained stable over the study period. In 1992, the rate of failure was 5.9% (2.0–13.3%) compared with 6.4% (3.7–24.1%) in 2008 (P=.89, nonsignificant) (Fig. 2). Furthermore, no significant variation in failure rate was noticed between the different centers included in the registry (data not shown). Univariable analysis showed no statistical difference with respect to basic characteristics between cases successfully treated and cases in which surgical treatment failed (Table 1).
When analyzing by subgroups according to hCG level, we found a statistically significant risk of failure in patients in whom preoperative serum hCG levels were 1,960 international units/L or greater (OR 1.8, 95% CI 1.1–2.8, P=.02). For patients with preoperative levels of hCG 1,960 international units/L or greater, the rate of treatment failure was 8.6% (5.9–11.2%), whereas in patients with hCG titers below this level, the failure rate was 5.1% (3.5–6.6%; P=.03). When variables with P<.20 were subjected to multivariable analysis (Table 2), only an hCG level 1,960 international units/L or greater remained significantly associated with the failure rate (P=.02).
The prognostic accuracy of this cutoff was evaluated by the receiver operating characteristic curve (Fig. 3). The area under the receiver operating characteristic curve was 0.57 (95% CI 0.55–0.60, P=.03). The sensitivity and specificity were 47% (35.3–58.5%) and 67% (64.0–69.5%), respectively. The positive and negative likelihood ratios were 1.4 and 0.8, respectively.
Laparoscopic management of ectopic pregnancy has gained wide acceptance and it is considered today as the “gold standard” technique in the treatment of this pathology.6–12 Surgical strategies can be radical (salpingectomy) or conservative (salpingostomy), but to date there is no agreement about which is the optimal procedure.24,25 Several nonrandomized trials have compared both approaches with conflicting results.26–30 However, there is some evidence that favors conservative approach in terms of fertility prognosis.14–16
On the other hand, the most common complication and the major reason for secondary intervention after conservative management is persistent ectopic pregnancy.31 It results from incomplete removal of trophoblast with persistent serum hCG.17–19 Obviously, a reliable method of preoperative prediction and detection of those patients at risk for developing persistent ectopic pregnancy is desirable, because a more radical approach could be considered in these cases.
Several factors has been proposed as predictors of failure for conservative surgical management of ectopic pregnancy.17,32–36 Nevertheless, different studies have yielded conflicting results.19,37 This discrepancy may be explained by the different definitions of failure, patient selection, and different operative skills.
Failure rates vary widely among published literature from 5% to 29%.17,31 In our study, we found a failure rate of 6.6%. It compares favorably with most previous reports and it is one of the lowest reported. Although in concordance with previous studies,1,34,35 we have found a direct correlation between the magnitude of hCG level and risk of persistent disease, the strength of our study is that it was conducted in a general population without any selection bias.
Nevertheless, our results indicate a large overlap demonstrated by the low sensitivity and specificity obtained. Moreover, the calculated likelihood ratios were not enough to generate important differences between pretest and posttest probabilities. Based on these considerations, and the fact that when hCG 1,960 international units/L or greater, the failure rate is still very low (8.6%), we think that this hCG cutoff lacks medical relevance and has a limited prognostic value to be used in clinical practice.
In absence of clinically relevant predictive factors of failure for a conservative surgical technique by laparoscopy, we hypothesize that both a standardized surgical technique and the use of appropriate instrumentation are recommended to achieve lower failure rates and reduce the probability of persistent ectopic pregnancy. Our surgical technique remains unchanged since the 1980s and has been taught and learned systematically under the same principles all these years. On the other hand, it is noteworthy that faulty equipment and use of inappropriate instrumentation have been cited as reasons for conversion38 or change in surgical technique.39
Salpingotomy should be always performed using a fine monopolar diathermy needle. We disagree with previous reports that suggest that surgical outcomes are not influenced by the surgical technique38,40 and that the choice of operative technique should be based on available instrumentation or surgeon preference.38 Based on the concept of “current density,”41 the current concentration rises inversely proportional to electrode surface. The use of monopolar scissors or other devices of greater surface leads to a less precise cutting limit and unnecessary thermal damage of surrounding tissue. The use of a fine monopolar needle, as a result of its minimal surface, allows clean and the most precise cutting of the three tubal layers, avoiding further tissue damage.
As previously described,3–5 linear salpingotomy must be performed along the antimesenteric border for preserve tubal vascularization. The incision should be done over the ectopic pregnancy, reaching the proximal (medial) portion of the hematosalpinx. This is very important because one study42 noted trophoblastic tissue to be implanted medial to the salpingotomy site in tubes that had been excised after the diagnosis of persistent ectopic pregnancy. These findings suggest that surgeons may not remove adequately the tissue medial to the site of the “bulge” within the tube.
Salpingostomy must be large enough (10–15 mm) to allow the introduction of a 10-mm cannula and extraction of trophoblast without difficulty through it. We discourage the use of tubal expression (“milking”) without associated salpingotomy, because this procedure is associated with a higher rate of persistent ectopic pregnancy.4,5,43
We systematically left the salpingostomy open to heal by secondary intention to decrease the risk of obstruction and allow better healing of mucosal folds.15 Moreover, according to previous reports,44 fertility outcomes are better if salpingostomy is left open. In addition, laparoscopic suturing is time-consuming and it does not have additional benefits.45
In conclusion, although persistent ectopic pregnancy could be predicted according to pretherapeutic hCG level, the prognostic accuracy of this parameter seems limited. Despite this, we have reported low failure rates in a general population by using a standardized technique developed more than 30 years ago. It underscores the importance of teaching operative laparoscopy to residents who are able to master the technique and benefit greatly from the experience in a tutorial fashion. It is hoped that this study will encourage gynecologists and residency training programs to invest in the training and equipment necessary to provide the optimal endoscopic approach to patients with ectopic pregnancy.
1. Walker JJ. Ectopic pregnancy. Clin Obstet Gynecol 2007;50:89–99.
2. Practice Committee of the American Society for Reproductive Medicine. Early diagnosis and management of ectopic pregnancy. Fertil Steril 2004;82:S146–8.
3. Bruhat M, Manhes H, Choukroun J, Suzanne F. Experimental laparoscopic treatment of ectopic pregnancy. Rev Fr Gynecol Obstet 1977;72:667–74.
4. Mage G, Manhes H, Pouly JL, Jacquetin B, Bruhat MA. Methods and results of treatment by laparoscopy of tubal pregnancy. A report on 78 cases. Gynecologie 1980;31:157–61.
5. Bruhat MA, Manhes H, Mage G, Pouly JL. Treatment of ectopic pregnancy by means of laparoscopy. Fertil Steril 1980;33:411–4.
6. Vermesh M, Silva PD, Rosen GF, Stein AL, Fossum GT, Sauer MV. Management of unruptured ectopic gestation by linear salpingostomy: a prospective, randomized trial of laparoscopy versus laparotomy. Obstet Gynecol 1989;73:400–4.
7. Lundorff P, Thorburn J, Hahlin M, Kallfelt B, Lindblom B. Laparoscopic surgery in ectopic pregnancy. A randomized trial versus laparotomy. Acta Obstet Gynecol Scand 1991;70:343–8.
8. Murphy AA, Nager CW, Wujek JJ, Kettel LM, Torp VA, Chin HG. Operative laparoscopy versus laparotomy for the management of ectopic pregnancy: a prospective trial. Fertil Steril 1992;57:1180–5.
9. Gray DT, Thorburn J, Lundorff P, Strandell A, Lindblom B. A cost-effectiveness study of a randomized trial of laparoscopy versus laparotomy for ectopic pregnancy. Lancet 1995;345:1139–43.
10. Garry R. The laparoscopic treatment of ectopic pregnancy; the long road to acceptance. Gynaecol Endosc 1996;5:65–8.
11. Lo L, Pun TC, Chan S. Tubal ectopic pregnancy: an evaluation of laparoscopic surgery versus laparotomy in 614 patients. Aust N Z J Obstet Gynaecol 1999;39:185–7.
12. Hajenius PJ, Mol F, Mol BW, Bossuyt PM, Ankum WM, van der Veen F. Interventions for tubal ectopic pregnancy. The Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD000324. DOI: 10.1002/14651858.CD000324.pub2.
13. Mol BW, Hajenius PJ, Engelsbel S, Ankum WM, Hemrika DJ, van der Veen F, et al. Is conservative surgery for tubal pregnancy preferable to salpingectomy? An economic analysis. Br J Obstet Gynaecol 1997;104:834–9.
14. Sherman D, Langer R, Sadovsky G, Bukovsky I, Caspi E. Improved fertility following ectopic pregnancy. Fertil Steril 1982;37:497–502.
15. Pouly JL, Mahnes H, Mage G, Canis M, Bruhat MA. Conservative laparoscopic treatment of 321 ectopic pregnancies. Fertil Steril 1986;46:1093–7.
16. Bangsgaard N, Lund CO, Ottesen B, Nilas L. Improved fertility following conservative surgical treatment of ectopic pregnancy. BJOG 2003;110:765–70.
17. Seifer DB, Gutmann JN, Doyle MB, Jones EE, Diamond MP, DeCherney AH. Persistent ectopic pregnancy following laparoscopic linear salpingostomy. Obstet Gynecol 1990;76:1121–5.
18. Dwarakanath LS, Mascarenhas L, Penketh RJ, Newton JR. Persistent ectopic pregnancy following conservative surgery for tubal pregnancy. Br J Obstet Gynaecol 1996;103:1021–4.
19. Lund CO, Nilas L, Bangsgaard N, Ottesen B. Persistent ectopic pregnancy after linear salpingotomy: a non-predictable complication to conservative surgery for tubal gestation. Acta Obstet Gynecol Scand 2002;81:1053–9.
20. Coste J, Job-Spira N, Aublet-Cuvelier B, Germain E, Glowaczower E, Fernandez H, et al. Incidence of ectopic pregnancy. First results of a population-based register in France. Hum Reprod 1994;9:742–5.
21. Coste J, Aublet-Cuvelier B, Bouyer J, Germaine, Job-Spira N. Evaluation of the completeness of the Auvergne register of ectopic pregnancy with the capture–recapture method. Rev Epidemiol Sante Publique 1995;43(suppl 1):10.
22. Hook EB, Regal RR. The value of capture–recapture methods even for apparent exhaustive surveys. The need for adjustment for source of ascertainment intersection in attempted complete prevalence studies. Am J Epidemiol 1992;135:1060–7.
23. Pouly JL, Chapron C, Manhes H, Canis M, Wattiez A, Bruhat MA. Multifactorial analysis of fertility after conservative laparoscopic treatment of ectopic pregnancy in a series of 223 patients. Fertil Steril 1991;56:453–60.
24. Parker J, Bisits A. Laparoscopic surgical treatment of ectopic pregnancy: salpingectomy or salpingostomy? Aust N Z J Obstet Gynaecol 1997;37:115–7.
25. Clausen I. Conservative versus radical surgery for tubal pregnancy. A review. Acta Obstet Gynecol Scand 1996;75:8–12.
26. Tuomivaara L, Kauppila A. Radical or conservative surgery for ectopic pregnancy? A follow-up study of fertility of 323 patients. Fertil Steril 1988;50:580–3.
27. dela Cruz A, Cumming DC. Factors determining fertility after conservative or radical surgical treatment for ectopic pregnancy. Fertil Steril 1997;68:871–4.
28. Mol BW, Matthijsse HC, Tinga DJ, Huynh T, Hajenius PJ, Ankum WM, et al. Fertility after conservative and radical surgery for tubal pregnancy. Hum Reprod 1998;13:1804–9.
29. Bouyer J, Job-Spira N, Pouly JL, Coste J, Germain E, Fernandez H. Fertility following radical, conservative-surgical or medical treatment for tubal pregnancy: a population-based study. BJOG 2000;107:714–21.
30. Dubuisson JB, Morice P, Chapron C, De Gayffier A, Mouelhi T. Salpingectomy—the laparoscopic surgical choice for ectopic pregnancy. Hum Reprod 1996;11:1199–203.
31. Seifer DB. Persistent ectopic pregnancy: an argument for heightened vigilance and patient compliance. Fertil Steril 1997;68:402–4.
32. Nathorst-Böös J, Rafik Hamad R. Risk factors for persistent trophoblastic activity after surgery for ectopic pregnancy. Acta Obstet Gynecol Scand 2004;83:471–5.
33. Spandorfer SD, Sawin SW, Benjamin I, Barnhart KT. Postoperative day 1 serum human chorionic gonadotropin level as a predictor of persistent ectopic pregnancy after conservative surgical management. Fertil Steril 1997;68:430–4.
34. Hagström HG, Hahlin M, Bennegård-Edén B, Sjöblom P, Thornburn J, Lindblom B. Prediction of persistent ectopic pregnancy after laparoscopic salpingostomy. Obstet Gynecol 1994;84:798–802.
35. Fujishita A, Khan KN, Kitajima M, Hiraki K, Miura S, Ishimaru T, et al. Re-evaluation of the indication for and limitation of laparoscopic salpingotomy for tubal pregnancy. Eur J Obstet Gynecol Reprod Biol 2008;137:210–6.
36. Seifer DB, Gutmann JN, Grant WD, Kamps CA, DeCherney AH. Comparison of persistent ectopic pregnancy after laparoscopic salpingostomy versus salpingostomy at laparotomy for ectopic pregnancy. Obstet Gynecol 1993;81:378–82.
37. Billieux MH, Petignat P, Anguenot JL, Campana A, Bischof P. Early and late half-life of human chorionic gonadotropin as a predictor of persistent trophoblast after laparoscopic conservative surgery for tubal pregnancy. Acta Obstet Gynecol Scand 2003;82:550–5.
38. DeCherney AH, Diamond MP. Laparoscopic salpingostomy for ectopic pregnancy. Obstet Gynecol 1987;70:948–50.
39. Courdier S, Garbin O, Hummel M, Thoma V, Ball E, Favre R, et al. Equipment failure: causes and consequences in endoscopic gynecologic surgery. J Minim Invasive Gynecol 2009;16:28–33.
40. Milad MP, Klein E, Kazer RR. Preoperative serum hCG level and intraoperative failure of laparoscopic linear salpingostomy for ectopic pregnancy. Obstet Gynecol 1998;92:373–6.
41. Pearce JA. Electrosurgery. London (UK): Chapman and Hall; 1986.
42. Stock RJ. Persistent tubal pregnancy. Obstet Gynecol 1991;77:267–70.
43. Chapron C, Querleu D, Crépin G. Laparoscopic treatment of ectopic pregnancies: a one hundred cases study. Eur J Obstet Gynecol Reprod Biol 1991;41:187–90.
44. Tulandi T, Guralnick M. Treatment of tubal ectopic pregnancy by salpingotomy with or without tubal suturing and salpingectomy. Fertil Steril 1991;55:53–5.
45. Fujishita A, Masuzaki H, Khan KN, Kitajima M, Hiraki K, Ishimaru T. Laparoscopic salpingotomy for tubal pregnancy: comparison of linear salpingotomy with and without suturing. Hum Reprod 2004;19:1195–200.
© 2010 by The American College of Obstetricians and Gynecologists.
Figure. No caption available.