Laparoscopic ablation is not necessary for minimal or mild lesions in endometriosis associated subfertility

Endometriosis, defined as the presence of endometrial glands and stroma at ectopic sites, is still not fully understood. The relation of minimal or mild endometriosis to subfertility is not established. The association is not necessarily cause and effect. Hence, the concept that initial endometriosis should always be treated to avoid worsening of the condition is controversial (1–5). Minimal/mild endometriosis could represent a temporary phase in an ongoing process that usually results in cytolysis of recently implanted endometrial cells, whereas in a few immunologically ‘tolerant’ subjects, nodular, cystic and infiltrating lesions develop, with eventual progression to moderate and severe stages. Endometriosis prevalence varies widely, being seen more frequently among women investigated for infertility (21%) than among those undergoing sterilization (6%). Among those being investigated for chronic abdominal pain, the incidence of endometriosis is 15%, while among those undergoing abdominal hysterectomy, it can be as high as 25% (6). The gold standard test to diagnose endometriosis is the direct visualization of classical or subtle lesions at laparoscopy. In one small randomized controlled trial (RCT) where repeat laparoscopy was performed after 12 months in the women treated with placebo, endometrial deposits resolved spontaneously in a quarter, deteriorated in nearly half, and were unchanged in the remainder (7). Whether minimal endometriosis is a condition that is frequently self-limited or resolves spontaneously or not, we still face a problem. Could ablation of minimal or mild endometriosis be associated with an increase in pregnancy rate? This is the hypothesis to be tested. Conventional treatments for endometriosis aim to remove or decrease deposits of ectopic endometrium. They achieve this either by inducing atrophy within the hormonally dependent ectopic endometrium, or by destroying the endometriotic implant. Medical treatment options for endometriosis include hormonal drugs such as the combined oral contraceptive, progestogens, duphaston, danazol, gestrinone or gonadotrophin releasing hormone analogs for pain relief. The aim of therapy is to ‘switch off ovarian function’. Their role in infertility treatment has been reviewed in a Cochrane systematic review (8) which concluded that there is no evidence to support their use in women with endometriosis who wish to conceive. While these approaches continue to be useful for the management of endometriosis associated pain, they may do more harm than good in women whose major concern is fertility. For the six months or more of treatment, women are forced to be temporarily infertile, losing valuable opportunities for treatment independent conception. Commonly used ovulation suppression agents also have significant adverse effects, including weight gain, hot flushes and osteoporosis. The other option for women with endometriosis, who wish to conceive, is surgical excision or ablation of deposits of endometriosis. The surgery may be performed laparoscopically including excision, laser or diathermy ablation and adhesiolysis. A prospective cohort analysis was conducted (9) to analyze results from 579 women with endometriosis to evaluate the role of surgery in the treatment of endometriosis associated with infertility. Interventions consisted of no treatment, medical treatment, or surgical treatment by laparoscopy or laparotomy. The main outcome measure was pregnancy rates. For minimal and mild disease, no treatment, laparoscopy, and laparotomy had equivalent 3-year estimated cumulative life-table pregnancy rates (67%±12%, 68%±4%, and 74%±8%, respectively), that were higher than medical treatment pregnancy rates (p=0.003). The authors urged for prospective randomized trials to be performed to confirm these findings. Marcoux et al. (10) conducted a randomized controlled trial to reach a clear evidence on ablation of minimal or mild endometriosis. They studied 341 infertile women 20 to 39 years of age with minimal or mild endometriosis. During diagnostic laparoscopy the women were randomly assigned to undergo resection or ablation of visible endometriosis or diagnostic laparoscopy only. They were followed for 36 weeks after the laparoscopy or, for those who became pregnant during that interval, for up to 20 weeks of pregnancy. Among the 172 women who had resection or ablation of endometriosis, 50 became pregnant and had pregnancies that continued for 20 weeks or longer, as compared with 29 of the 169 women in the diagnostic-laparoscopy group (cumulative probabilities, 30.7% and 17.7%, respectively; p=0.006). The corresponding rates of fecundity were 4.7 and 2.4 per 100 person-months (rate ratio, 1.9; 95% confidence interval, 1.2–3.1). Fetal losses occurred in 20.6% of all the recognized pregnancies in the laparoscopic-surgery group and in 21.6% of all those in the diagnostic-laparoscopy group (p=0.91). Four minor operative complications (intestinal contusion, slight tear of the tubal serosa, difficult pneumoperitoneum, and vascular trauma) were reported (three in the surgery group and one in the control group). The authors concluded that laparoscopic resection or ablation of minimal and mild endometriosis enhances fecundity in infertile women. Two years later, a group from Italy (11) reported another randomized controlled trial to evaluate the available evidence. Eligible women were randomly assigned to resection or ablation of visible endometriosis (54 patients) or diagnostic laparoscopy only (47 patients). After laparoscopy women tried to conceive spontaneously for one year (follow-up period). A total of five women withdrew from the study: three for personal reasons, and two were lost to follow-up. Considering 51 women in the resection/ablation and 45 in the no-treatment group who ended the follow-up period, 12 (24%) in the resection/ablation group and 13 (29%) in the no treatment group conceived; the difference was not significant. Two spontaneous abortions were observed in the resection/ablation group and three in the no-treatment one. Thus the one year birth rate was ten out of 51 women (19.6%) in the resection/ablation group and ten out of 45 women (22.2%) in the no-treatment group. The results of this study did not support the hypothesis that ablation of endometriotic lesions markedly improves fertility rates. Two points should be noticed in these two trials. First, in order to be able to conclude that removing endometriosis is effective, it would be better not to do the adhesiolysis, which can be considered as a co-intervention. However, this was not done. The second point is that the patients were informed about the result of procedure done (ablation or no ablation) immediately after laparoscopy at their postoperative appointments. This could have a possible negative placebo effect on those in the expectant group or a positive placebo effect in those who had ablation. The Marcoux et al. trial (10) stands as the largest RCT on endometriosis, and many articles mentioned it to document the efficacy of surgery in minimal or mild endometriosis (12). If we consider only late pregnancies in the these two trials (50/172 in the ablation group versus 29/169 in the no surgery group in the Canadian study and 10/54 versus 10/47 respectively in the Italian study), the OR would be 1.64 (95% CI, 1.02–2.67) noticing that the lower confidence interval limit is too close to unity. We can also express the results more practically in terms of the number of women to undergo surgery to achieve an additional pregnancy. In this case, even taking into account only the results of the Canadian trial, the benefit of laparoscopic ablation appears less encouraging. In fact, eight women with minimal to mild endometriosis need to undergo laparoscopic ablation to achieve an additional late pregnancy. However, considering that we cannot identify women with endometriosis preoperatively, and that the proportion of subjects with endometriosis in the Canadian series of patients undergoing laparoscopy for unexplained infertility was a little less than 50%, the number needed to be treated doubles at least (13). Interestingly, the Canadian group has also conducted a well designed prospective cohort study (14) to assess whether infertile women with minimal or mild endometriosis have lower fecundity than women with unexplained infertility. Infertile women with minimal or mild endometriosis (n=168) were compared with women with unexplained infertility (n=263). Both groups were managed expectantly. The women were followed up for 36 weeks after the laparoscopy or, for those who became pregnant, for up to 20 weeks of the pregnancy. Fecundity was 18.2% in infertile women with minimal or mild endometriosis and 23.7% in women without endometriosis. The fecundity rate was 2.52 per 100 person-months in women with endometriosis and 3.48 per 100 person-months in women with unexplained infertility. The crude and adjusted fecundity rate ratios were 0.72 and 0.83 (95% confidence interval=0.53–1.32), respectively. Thus, the fecundity of infertile women with minimal or mild endometriosis is not significantly lower than that of women with unexplained infertility. Many investigators (15, 16) have wondered if minimal or mild endometriosis is really a disease that needs treatment. In conclusion, laparoscopic ablation for minimal or mild endometriosis associated subfertility seems to be of very limited efficacy. Exposing those women to unnecessary anesthesia and laparoscopic manipulations should not be done, except in the context of randomized controlled trials for further evaluation of the evidence.