Effect of salpingectomy on ovarian response to hyperstimulation during in vitro fertilization A meta analysis

Authors:
Minghui Fan, M.D., Lin Ma, M.D., Ph.D.

Abstract:

Objective:
To compare ovarian response to hyperstimulation during IVF between patients who did and did not undergo salpingectomy.

Design:
Meta-analysis.

Setting:
University-affiliated teaching hospital.

Patient(s):
Patients undergoing IVF who did and did not undergo salpingectomy.

Intervention(s):
None.

Main Outcome Measure(s):
The total dose of gonadotropin, duration of hyperstimulation, E level on the day of hCG injection, number of oocytes retrieved, and basal FSH level were evaluated because these reflect ovarian response.

Result(s):
Twenty-five studies were identified through searches conducted on PubMed, Cochrane Libraries, Ovid, Web of Science, Science Direct, China National Knowledge Infrastructure, and Wanfang Database through October 2015. The 25 studies included 1,935 patients who underwent salpingectomy and 2,893 who did not. Fixed-effects and random-effects models were used to calculate the overall combined risk estimates. The results of the meta-analysis suggest that salpingectomy impairs ovarian response to hyperstimulation. The total dose of gonadotropin was significantly increased after combined salpingectomy (inverse variance [IV] 0.10 [95% confidence interval (CI) 0.03, 0.16]; I2 = 30%) and bilateral salpingectomy (IV [95% CI] 0.23 [0.09, 0.37]; I2 = 36%). The number of oocytes retrieved decreased significantly after unilateral salpingectomy (IV [95% CI] −0.17 [−0.27, −0.06]; I2 = 31%) and bilateral salpingectomy (IV [95% CI] −0.20 [−0.32, −0.08]; I2 = 48%). In addition, a statistically significant reduction was found between the number of oocytes retrieved from the ipsilateral and contralateral ovary (IV [95% CI] 0.25 [−0.40, −0.10]; I2 = 48%). Finally, bilateral salpingectomy may lead to an increase in the FSH level (IV [95% CI] 0.39 [0.20, 0.59]; I2 = 0%). Heterogeneity moderators were identified by performing subgroup and sensitivity analyses. No evidence of publication bias was observed.

Conclusion(s):
This meta-analysis indicated that salpingectomy may impair ovarian response to hyperstimulation during IVF. Further high-quality research is needed to confirm our findings and to develop therapeutic methods that are alternatives to salpingectomy for maternal well-being.

  • Roberta Venturella

    We read with interest the meta-analysis recently published by Fan M. and Ma. L on the April issue of Fertility and Sterility on the effect of salpingectomy on ovarian response to hyperstimulation during in vitro fertilization (1), and we would like to comment on it.

    Until the end of the 20th century, salpingectomy has been considered a trivial appendix of more complex gynecological surgeries or as an “emergency” option to solve life-threatening conditions such as ruptured ectopic tubal pregnancies.

    In the last twenty years however, something has changed. Salpingectomy, indeed, achieved increasing consensus as a clinical standard both for women who require surgery for a benign pelvic pathology and as a permanent sterilization method (2). It has been determined on one side, by the publication by the Practice Committee of the American Society for Reproductive Medicine (ASRM) about the effect of salpingectomy for hydrosalpinx prior to in vitro fertilization (IVF) (3) reviewed by the 2015 committee opinion on the role of tubal surgery in the era of assisted reproductive technology (4) and on the other side, by the spread of the new theory that considers the distal Fallopian tube as the site of origin for ovarian and peritoneal serous cancers (5).

    In tubal factor infertility, when the cause is irreparable hydrosalpinx, IVF is now considered the first option rather than attempting to restore tubal function (4). The hydrosalpinges themselves, however, adversely affect IVF outcomes, by reducing the implantation rate and increasing the risk of miscarriage. Among the pathogenic mechanisms proposed, embryo-toxic effects, mechanical flushing and changes in endometrial receptivity are the most shared by reproductive gynecologists. According to these pathogenic theory, the rationale behind surgical treatment of hydrosalpinges prior to IVF is exactly to eliminate the negative effect of hydrosalpingeal fluid either by aspirating it (ultrasound-guided aspiration) or by removing the entire fallopian tubes (salpingectomy) or by isolating them from the uterine cavity (laparoscopic or hysteroscopic proximal occlusion).

    By these ways, indeed, the hydrosalpinx fluid is no longer able to reach the uterine cavity, in which embryos try to implant, and cannot exert its toxic effect on this delicate phase of pregnancy. In this view, everyone agrees that the correct method to verify the effectiveness of surgical treatments (as salpingectomy or tubal occlusion) compared with no intervention prior to IVF is to choose live birth rate or at least clinical pregnancy rate as the main study outcomes for such kind of evaluations.

    In February 2016, a network meta-analysis by Tsiami et al. (6) collected and studied seven randomized controlled trials on women with hydrosalpinx treated by ultrasound-guided aspiration of the fluid, or tubal occlusion or salpingectomy before IVF, compared to non-treated women. Their primary outcome was live birth, using ongoing pregnancy as a surrogate when live birth was not reported. Although the differences between the three interventions (i.e. salpingectomy, aspiration and occlusion) failed to reach statistical significance, for the outcome of ongoing pregnancy, both salpingectomy (RR 2.24, 95% CI 1.27-3.95) and proximal tubal occlusion (RR 3.22, 95% CI 1.27-8.14) appeared to be superior to no treatment (6).

    These findings are consistent with those of two previous meta-analysis on the topic (7,8), reporting an increased ongoing and clinical pregnancy rates with salpingectomy vs. no intervention (OR 2.14, 95% CI 1.23-3.73 and OR 2.31, 95% CI 1.48-3.62, respectively), an increase in clinical pregnancy rate with occlusion vs. no intervention (OR 4.66, 95% CI 2.47-10.01) (7) and no difference in the clinical pregnancy rates between salpingectomy and tubal occlusion (8).

    By the way, if it is known that the detrimental effect of hydrosalpinx is exerted on the implantation stage and it is clearly confirmed by the two-folds increased odd ratio for pregnancy rate in women in which the affected tube is removed, what is the rationale of evaluating the effect of salpingectomy on ovarian response to hyperstimulation during IVF? Maybe, if clear and unconfutable evidence that salpingectomy significantly reduces the ovarian response to FSH stimulation would be inferred, this could lead reproductive gynecologists to recommend to their patients a two-stage approach. First, ovarian hyperstimulation, egg collection, mature oocyte in vitro fertilization and blastocysts freezing; second stage, salpingectomy followed by thawed embryo transfer, after eliminating the negative effect of the affected tube on implantation.

    Before introducing such an approach, only applicable in IVF centers able to offer good prognosis cycles in modern and qualified laboratories able to ensure high success rates in cycles with thawed blastocysts, incontrovertible evidence are needed.

    Fan M. and Ma L. recently published their meta-analysis aimed to compare ovarian response to hyperstimulation during IVF between patients who did and did not undergo salpingectomy (1). Of the 25 studies included in the final analysis, 12 were in English and 13 in Chinese. As correctly reported by authors, moreover, 21 studies were retrospective, and four were prospective; no homogeneity in the IVF protocols was found, since 18 studies used long protocols, 3 used a short protocol, 3 used other not-specified protocols and 1 was unclear. This heterogeneity probably reduces the meaning of considering the total dose of gonadotropins and the duration of hyperstimulation as outcomes measure for their purpose; moreover, concerning basal FSH value, given its recognized inter and intra-cycles variability, it is currently considered the most indirect marker of ovarian reserve (9).

    Focusing on the number of oocytes retrieved, the meta-analysis demonstrated that, overall, their number after salpingectomy was not statistically significantly different from that of the control group (IV -0.09 [95% CI -0.20, 0.03]; p=.15) and had substantial evidence of heterogeneity (I2 =65%). Conversely, statistical significance seems to be founded in the comparisons among unilateral salpingectomy versus controls and bilateral salpingectomy versus controls. Unfortunately, however, of the 25 studies included, those two negatively influencing the results of these comparisons are chinese published articles, for which only abstract is available online (10,11). All the others studies report not significant differences among groups for this outcome.

    Again, the question is: how much should statistical significance influence our decision-making processes in the management of our patients? Is the mean difference of 2 to 5 oocytes reported in two retrospective studies enough for justifying our doubts about the efficacy of salpingectomy in enhancing the live birth rate in IVF patients affected by tubal pathologies?

    A different discussion is to focus the attention on the salpingectomy safety in term of overall health of our patients. In this case, the outcomes to be evaluated are the intra- and post-operative complications and the effect of surgery on ovarian reserve, as assessed by objective and direct parameters, such as a complete basal hormonal assessment and ultrasonographic evaluation of antral follicles and ovarian vascularization. Many authors are publishing their findings in this area (8,12-18) showing that salpingectomy is not associated to perioperative complications and does not have negative effects on the ovarian function, at least 3 months after surgery. In this regard, the evaluation of age at menopause of patients treated with salpingectomy compared with controls would be the conclusive proof of the safety of the technique, because if there were no significant differences between the groups, salpingectomy could definitely be considered safe.

    Up to now, also considering that in 2015 both the American College of Obstetricians and Gynecologists and the American Cancer Society recommended that surgeons should discuss the potential benefits of the prophylactic removal of Fallopian tubes during surgeries for benign pathologies with every woman at population risk for ovarian cancer (19,20), caution is required in reporting any indirect negative effects of salpingectomy. Conversely we suggest that in the next years all efforts should be focused on rigorous and objective studies on the medium and long term consequences of salpingectomy, both in terms of live birth rates after IVF than in terms of general women health.

    All the authors report no conflict of interest.

    References

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