The authors have declared that no competing interests exist.
The impairment of the ovarian response in
Case–control study (Canadian Task Force Classification II-2).
A tertiary hospital–affiliated fertility center.
Fifty-four women aged <35 years with a history of salpingectomy and 59 age-matched women without tubal disease.
Gonadotropin-releasing hormone antagonist protocol for controlled ovarian stimulation and transvaginal oocyte retrieval.
The antral follicle count (AFC), anti-Müllerian hormone (AMH) levels, and the number of retrieved oocytes were significantly lower in women with prior salpingectomy than in women without tubal disease. Day-3 follicle-stimulating hormone (FSH) levels, total gonadotropin dosage, and stimulation days did not significantly differ between the groups. The indications of salpingectomy (i.e., hydrosalpinx and ectopic pregnancy) did not differ significantly in terms of ovarian response or reserve among women with salpingectomy history. A history of salpingectomy and other factors related to ovarian response in IVF, such as age, AMH, AFC, day-3 FSH, and total gonadotropin dose, were significantly correlated with the number of oocytes retrieved by univariate regression analysis. In the multivariate-adjusted model after controlling all the above-mentioned variables, only AFC and AMH levels continued to exhibit significant associations with the number of retrieved oocytes. In a subgroup analysis, the negative impact of prior salpingectomy on the number of retrieved oocytes was especially significant in women with suboptimal ovarian reserves (defined as AMH < 4 ng/mL), regardless of the indication of salpingectomy or whether salpingectomy was bilateral or unilateral.
A negative effect on the number of retrieved oocytes in the subsequent IVF cycle after salpingectomy is more likely in women aged <35 years with suboptimal ovarian reserve. Nevertheless, postsurgical AMH and AFC levels still possess a more direct predictive value on ovarian response than the history of salpingectomy.
Tubal factor infertility is among the most common causes of female infertility, affecting approximately 30%–35% of women with infertility [
A hydrosalpinx occurs when a blocked fallopian tube fills with fluid, and it is a common disease in women who have undergone
Ectopic tubal pregnancy is associated with chronic salpingitis, and typical treatment includes salpingectomy, especially when evidence of rupture is present [
A randomized controlled trial of women with hydrosalpinges [
Nonetheless, most meta-analyses have been unable to demonstrate a significant detrimental effect of salpingectomy on ovarian reserve and ovarian response in IVF, regardless of the indications of salpingectomy [
In a study comparing women with infertility with and without history of salpingectomy for known tubal disease [
The outcomes considered in this study were the indication of salpingectomy, bilateral versus unilateral salpingectomy, and distinct levels of baseline ovarian reserve, which may have influenced the effect of salpingectomy on the number of retrieved oocytes.
This retrospective case–control study was approved by the Institutional Review Board of Shin Kong Wu Huo-Shih Memorial Hospital (Approval number: 20210704R). All clinical data were fully anonymized before we accessed them and the inform consent was waived because of the retrospective nature.
The research was conducted in the Infertility Center of the Department of Obstetrics and Gynecology at Shin Kong Wu Huo-Shih Memorial Hospital from January 2012 through December 2019. During this period, 1096 patients aged under 35 years received IVF treatment in our center, including 102 patients with a history of salpingectomy. For the final analysis, the study group consisted of 54 participants after women who did not meet our inclusion criteria or lacked complete surgical records were excluded. Another 59 participants were randomly selected as age-matched controls (by 3-year age strata) from a consecutive series of 606 women with conventional hysterosalpingography results; these participants received IVF because of male fertility factors or unexplained infertility. For all the recruited participants, the data for controlled ovarian stimulations were only collected from the first IVF cycle.
The study group was further divided into subgroups according to the indication for salpingectomy (hydrosalpinx or ectopic pregnancy) and the type of salpingectomy (bilateral or unilateral). The inclusion criteria of all the enrolled control and study participants were as follows: (1) aged 20–34 years, (2) had a regular menstrual cycle, and (3) treated with a gonadotropin-releasing hormone (GnRH) antagonist protocol. Patients were excluded if they had a history of ovarian surgery or diseases that affect ovarian function, namely endometriosis, ovarian tumors, polycystic ovarian syndrome, and autoimmune disease. Patients were excluded from the control group if tubal factors were present.
All the enrolled patients who required tubal surgery received laparoscopic salpingectomy from an experienced gynecologic surgeon who endeavored to incise the smallest possible area within the mesosalpinges. We excluded patients who received segmental salpingectomy for severe pelvic adhesion or other inoperable conditions.
All the enrolled patients were treated with an individualized GnRH antagonist protocol [
The number of retrieved oocytes, total administered dose of gonadotropin, and total days of ovarian stimulation were recorded. The biomarkers anti-Müllerian hormone (AMH), day-3 FSH, and AFC on menstrual cycle day 2 or 3 were also measured before patients entered the IVF cycle to predict ovarian reserve. Subgroup analyses were conducted to evaluate the association between the number of retrieved oocytes and salpingectomy in women with infertility undergoing IVF with various baseline ovarian reserves. The cutoff value for AFC (12 follicles) was based on the calculated median AFC of all enrolled patients, and the cutoff value for AMH (4 ng/mL) was based on the reported 75th percentile of AMH levels of generally healthy Chinese women aged 35 years. The AMH levels between 35 to 36 year-old Chinese women lies between 4.229 to 3.973 ng/mL in the 75th percentile [
Numeric variables are presented as untransformed means ± standard deviations unless indicated otherwise. Between-group comparisons were conducted using a Mann–Whitney
Fifty-four women in their first IVF cycle with a history of salpingectomy along with 59 age-matched controls without prior tubal disease were included in the final analysis. Among the women with a history of salpingectomy, the indication for salpingectomy was ectopic pregnancy in 26 patients and hydrosalpinx in 28 patients. As detailed in
Study group (with history of salpingectomy) | Control group (without tubal diseases) | |||||
---|---|---|---|---|---|---|
Reason for salpingectomy | Ectopic pregnancy | Hydrosalpinx | All | |||
26 | 28 | - | 54 | 59 | - | |
28.6 ± 4.9 | 30.8 ± 2.6 | 0.09 | 29.7 ± 4.0 | 29.3 ± 1.8 | 0.25 | |
20.9 ± 2.5 | 20.0 ± 4.5 | 0.67 | 20.4 ± 3.7 | 20.8 ± 2.1 | 0.76 | |
11.3 ± 7.2 | 10.4 ± 6.2 | 0.48 | 10.8 ± 6.6 | 13.2 ± 5.2 | 0.005 | |
7.6 ± 1.8 | 7.5 ± 2.5 | 0.37 | 7.5 ± 2.2 | 7.4 ± 1.7 | 0.93 | |
5.4 ± 2.7 | 5.2 ± 3.9 | 0.44 | 5.3 ± 3.3 | 6.6 ± 3.5 | 0.039 | |
2303.8 ± 763.6 | 2528.6 ± 1051.1 | 0.59 | 2420.4 ± 922.4 | 2193.2 ± 647.3 | 0.30 | |
9.8 ± 1.2 | 9.9 ± 1.3 | 0.77 | 9.8 ± 1.3 | 9.9 ± 1.3 | 0.59 |
BMI: body mass index; AFC: antral follicle count; AMH: anti-Müllerian hormone; FSH: follicle-stimulating hormone.
* Statistical comparisons between participants with distinct indications of salpingectomy.
** Statistical comparisons between the control and study groups.
The univariate analysis suggested that the number of retrieved oocytes was significantly and negatively associated with history of salpingectomy, age, day-3 FSH levels, and total gonadotropin dose, whereas a significant positive association was observed between the number of retrieved oocytes and AFC and AMH levels (
Univariate analysis | Multivariate analysis | |||||||
---|---|---|---|---|---|---|---|---|
Age adjusted | BMI adjusted | Full model | ||||||
Variables | β | β | β | β | ||||
-0.2405 | 0.005 | -0.2353 | 0.005 | -0.2369 | 0.007 | -0.0415 | 0.56 | |
-0.8390 | 0.004 | - | - | -0.8574 | 0.034 | -0.0053 | 0.99 | |
-0.1391 | 0.45 | -0.1579 | 0.38 | - | - | -0.1152 | 0.37 | |
0.5887 | <0.001 | 0.5744 | <0.001 | 0.5791 | <0.001 | 0.3441 | <0.001 | |
-0.4541 | 0.008 | -0.5124 | 0.002 | -0.4125 | 0.018 | -0.1934 | 0.18 | |
0.4335 | <0.001 | 0.4366 | <0.001 | 0.4309 | <0.001 | 0.2726 | <0.001 | |
-0.4881 | <0.001 | -0.4688 | <0.001 | -0.4648 | <0.001 | -0.1442 | 0.39 | |
0.3339 | 0.34 | 0.3461 | 0.34 | 0.3586 | 0.32 | 0.7669 | 0.021 |
BMI: body mass index; AFC: antral follicle count; AMH: anti-Müllerian hormone; FSH: follicle-stimulating hormone.
The number of retrieved oocytes was significantly lower in patients in the study group than in those without a history of salpingectomy (10.4 ± 5.2 vs. 12.2 ± 3.8,
(A) Total number of retrieved oocytes in IVF was significantly higher in the enrolled women as a whole than in those with a history of salpingectomy. Subgroup analysis of women with (B) AMH < 4 ng/mL and (C) AMH ≥ 4 ng/mL. The study and control groups comprised women with a history of salpingectomy and women without tubal disease, respectively. Values presented as mean ± SD and were provided in the minimal data set of supplementary files. Statistical analysis was conducted by Mann–Whitney
Study subjects (with history of salpingectomy) | Control subjects (without tubal diseases) | |||||
---|---|---|---|---|---|---|
Ectopic pregnancy | Hydrosalpinx | All | ||||
6.9 ± 2.9 | 6.0 ± 3.4 | 0.75 | 6.4 ± 3.1 | 9.9 ± 3.0 | 0.007 | |
12.8 ± 3.7 | 13.3 ± 5.8 | 0.96 | 13.1 ± 4.8 | 12.8 ± 3.7 | 0.52 | |
8.2 ± 2.9 | 8.0 ± 5.2 | 0.31 | 8.1 ± 4.4 | 10.2 ± 3.1 | 0.004 | |
12.8 ± 3.5 | 15.2 ± 5.3 | 0.30 | 13.8 ± 4.4 | 13.4 ± 3.7 | 0.56 |
AFC: antral follicle count; AMH: anti-Müllerian hormone.
* Statistical comparisons between participants with distinct indications of salpingectomy.
** Statistical comparisons between the control and study groups.
The women with salpingectomy history because of hydrosalpinx had a significantly lower retrieved oocyte number than the women without a history of tubal disease (
Comparison of the differences in the numbers of retrieved oocytes between women without tubal disease (control) and women with different indications for prior salpingectomy (i.e., hydrosalpinx and ectopic pregnancy) (A) in all enrolled participants, (B) in women with AMH < 4 ng/mL, and (C) in women with AMH ≥ 4 ng/mL. Values were provided in the minimal data set of supplementary files. Statistical analysis was by Kruskal–Wallis test with the Hochberg post hoc testing. AMH: anti-Müllerian hormone.
Differences in the retrieved oocyte numbers in women with bilateral salpingectomy, unilateral salpingectomy, and without salpingectomy (A) in all enrolled subjects, (B) in women with AMH < 4 ng/mL, and (C) in women with AMH ≥ 4 ng/mL. AMH: anti-Müllerian hormone.
In this study, the number of retrieved oocytes in young patients with a history of salpingectomy who were undergoing IVF was significantly lower than that in the controls without tubal disease. In addition, the subgroup analysis revealed that the reduction in the retrieved oocyte number related to prior salpingectomy was prominent in patients without optimal baseline ovarian reserve. This study investigated the effect of prior salpingectomy and its indications on the subsequent ovarian response in women undergoing IVF. To our knowledge, this is the first study of such topics that specifically focused on patients younger than 35-year-old who received a GnRH antagonist protocol for controlled ovarian stimulation, compared the study population with a control group that did not have underlying tubal disease, and examined the effect of baseline ovarian reserve.
Several studies have reported a beneficial effect of salpingectomy on embryo implantation and clinical pregnancy rate in women with infertility and hydrosalpinges [
Previous research has reported that a longer duration of ovarian stimulation and a higher dose of gonadotropin was required for IVF in women who underwent salpingectomy than in those who did not [
The present study demonstrates that women without an optimal baseline ovarian reserve may be more vulnerable to damage from salpingectomy. For women with an optimal ovarian reserve and a large follicle pool, a history of salpingectomy did not affect the number of retrieved oocytes in subsequent IVF cycles. Similar results were observed in a retrospective study [
The primary outcome in our study was actual retrieved oocyte number. We contend that to obtain more embryos, using retrieved oocyte number as a reference would be superior to using circulating surrogate markers of ovarian reserve. The number of retrieved oocytes was also positively correlated with pregnancy outcome. The number of retrieved oocytes in relation to the total dose of ovarian stimulation drugs could reflect the ovarian response. However, a retrospective study [
Along with concern about damage of periovarian vascular perfusion and potential thermal damage by an electrocauterization device during salpingectomy, underlying fallopian tube diseases that lead to hydrosalpinges and ectopic pregnancy may also contribute to impaired ovarian response. Pelvic inflammatory disease and mild peritoneal endometriosis are common causes of tubal adhesion or malfunction. In patients without prior surgical intervention, chronic pelvic inflammation and tubal obstruction reportedly reduce ovarian reserves, as indicated by lower AMH levels in these patients than in healthy women with infertility [
(DOCX)
PONE-D-21-34495
Prior Salpingectomy Impairs the Retrieved Oocyte Number in In Vitro Fertilization Cycles of Women Under 35 Years Old Without Optimal Ovarian Reserve : a retrospective study
PLOS ONE
Dear Dr. Ho,
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ACADEMIC EDITOR: This study investigating the association between the history of salpingectomy and the number of oocytes in women undergoing IVF has some issues that need to be addressed. Specifically, 2. the English needs a revision; 2. The authors should convince the reader that there were no selection biases; 3. Limits of the study needs to be discussed; 4. Several comparisons were performed. Please perform a Bonferroni's correction. All the issues raised by the Reviewers should be carefully addressed.
==============================
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Additional Editor Comments:
This study investigating the association between the history of salpingectomy and the number of oocytes in women undergoing IVF has some issues that need to be addressed. Specifically, 2. the English needs a revision; 2. The authors should convince the reader that there were no selection biases; 3. Limits of the study needs to be discussed; 4. Several comparisons were performed. Please perform a Bonferroni correction. All the issues raised by the Reviewers should be carefully addressed.
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Reviewers' comments:
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Reviewer #1: Yes
Reviewer #2: Yes
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Reviewer #1: The authors investigated the association between the history of salpingectomy and the number of oocytes in young women undergoing IVF. They found that the number of retrieved oocytes was significantly lower in patients with a history of salpingectomy, and the influence was more evident in women with AMH<4.
The paper provides important data, but it still needs some revision to be acceptable for the PLOS ONE.
#1 It is unclear why the author investigated women under 35 years old. Ref No.13 showed no influence of salpingectomy on AFC in women under 35. Please clarify in the Introduction.
#2 A previous retrospective study (shown below) also showed the influence of salpingectomy on ovarian reserve in IVF-ET patients. The study showed a negative effect on AMH but no impact on retrieved oocytes. The number of retrieved oocytes was the primary outcome of the present study. Please discuss the impact on retrieved oocytes at great length in the Discussion.
1. Ye XP, Yang YZ, Sun XX. A retrospective analysis of the effect of salpingectomy on serum antiMullerian hormone level and ovarian reserve. American journal of obstetrics and gynecology. 2015;212(1):53 e1-10.
#3 In Table 2, the history of salpingectomy is not statistically significant in full model multivariate analysis. The author should explain this point.
#4 The author should explain the limitation of this study. The result was not conclusive. There are some limitations regarding retrospective design, sample size, or baseline difference between two groups. As mentioned in the Discussion, it is also possible that the baseline difference of AFC and AMH was not the result of salpingectomy but other pelvic conditions.
#5 In figure 2 and 3, p-values of Kruskal–Wallis tests are needed. The correction method should be shown to compare groups (e.g., Bonferroni correction).
#6 A significant figures of p-values are not the same. (Figure 1A p=0.006, Figure 2 and 3 p<0.05, and p<0.01 are used in tables)
#7 The author should decrease tone, especially in conclusion, because this study has several limitations.
Reviewer #2: Dear Authors,
The subject of the study is current. A clear, simple and understandable writing language was used in the article. I believe it will benefit the reader. This is a good study comparing the number of oocytes collected after salpingectomy. Congratulations to the authors.
Below are my recommendations for the study.
Best regards
- Some english grammar mistakes should be corrected.
-I suggest that some studies comparing the histopathological effects of salpingectomy and proximal tubal occlusion procedures on ovarian tissue should be given as examples [e.g. Atilgan R, Pala Ş, Kuloğlu T, Şanli C, Yavuzkir Ş, Özkan ZS. Comparison of the efficacy between bilateral proximal tubal occlusion and total salpingectomy on ovarian reserve and the cholinergic system: an experimental study. Turk J Med Sci. 2020 Jun 23;50(4):1097-1105. doi: 10.3906/sag-2002-179. ..................
Atilgan R, Kuloğlu T, Boztosun A, Orak U, Baspinar M, Can B, Sapmaz E. Investigation of the effects of unilateral total salpingectomy on ovarian proliferating cell nuclear antigen and follicular reserve: experimental study. Eur J Obstet Gynecol Reprod Biol. 2015 May;188:56-60. doi: 10.1016/j.ejogrb.2015.02.028.]
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Reviewer #1: No
Reviewer #2: Yes: Remzi Atılgan
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Comment Responses and Rebuttal
We greatly appreciated the editor and reviewers’ valuable comments. We have revised our manuscript accordingly and for adherence to the journal requirements. Our point-by-point responses to your comments are as follows.
# Additional Editor Comments
This study investigating the association between the history of salpingectomy and the number of oocytes in women undergoing IVF has some issues that need to be addressed. Specifically,
Comment 1. The English needs a revision.
Response 1: We apologize for the grammar mistakes in our manuscript. We have commissioned the help of an English-language editing team to revise our manuscript. We have attached the certificate for this service as a supplementary file.
Comment 2. The authors should convince the reader that there were no selection biases.
Response 2: In this study conducted from January 2012 through December 2019, all the women with infertility who met the inclusion and exclusion criteria of the study underwent oocyte retrieval at the Department of Obstetrics and Gynecology at Shin Kong Wu Huo Shih Hospital and were enrolled consecutively for analysis. The age-matched control subjects were enrolled by 3-year age strata, with the first names on the lists selected. No patients were excluded from final analysis as outliers. We have avoided selection bias as much as possible by employing these methods, which we have further detailed in the “Materials and methods” section.
Comment 3. Limits of the study needs to be discussed.
Response 3: This study has several limitations, including its retrospective design, small sample size, and lack of measurement before salpingectomy. In addition, because we only selected women without underlying tubal disease as our controls, those women with tubal disease but without tubal surgery history were not considered in this study. We have addressed these limitations in our revised manuscript in the revised “Discussion” section, page 19 and 20, lines 388–394.
Comment 4. Several comparisons were performed. Please perform a Bonferroni correction.
Response 4: Because the Bonferroni test is reportedly too stringent to identify the between-group differences with such a small sample size, we reanalyzed the data by applying nonparametric Kruskal–Wallis test, with Hochberg method for post hoc testing instead; we have described these procedures in our revised “Statistical Analysis” section and in the revised versions of Figs 2 and 3.
# Reviewer 1’ s comments:
The authors investigated the association between the history of salpingectomy and the number of oocytes in young women undergoing IVF. They found that the number of retrieved oocytes was significantly lower in patients with a history of salpingectomy, and the influence was more evident in women with AMH<4.
The paper provides important data, but it still needs some revision to be acceptable for the PLOS ONE.
Comment 1. It is unclear why the author investigated women under 35 years old. Ref No.13 showed no influence of salpingectomy on AFC in women under 35. Please clarify in the Introduction.
Response 1:
Thank you for your comments and suggestions. In the study of Chen et al. (i.e., Ref 13), a lower AFC was only discovered in women with infertility who were aged 35–39 years in response to salpingectomy and not in those women under the age of 35 years. This may imply an age-related ovarian function decline that highlights the negative effect of salpingectomy on ovarian reserves. However, Chen et al. did not perform subgroup analyses to investigate whether the effect of salpingectomy was also more pronounced in women aged under 35 years with suboptimal ovarian reserves. Moreover, in the study of Chen et al., the researchers selected patients with tubal disease as controls; the effect of salpingectomy may thus have been reduced, with underlying disease possibly acting as a confounding factor that reduced ovarian reserves. We have further clarified this matter in the revised “Introduction” on page 6, lines 124–131).
Comment 2. A previous retrospective study (shown below) also showed the influence of salpingectomy on ovarian reserve in IVF-ET patients. The study showed a negative effect on AMH but no impact on retrieved oocytes. The number of retrieved oocytes was the primary outcome of the present study. Please discuss the impact on retrieved oocytes at great length in the Discussion.
1. Ye XP, Yang YZ, Sun XX. A retrospective analysis of the effect of salpingectomy on serum anti-Mullerian hormone level and ovarian reserve. American journal of obstetrics and gynecology. 2015;212(1):53 e1-10.
Response 2:
We have cited the reference as [24] and discussed it in the “Discussion” section on pages 18 and 19, lines 364–376 in our revised manuscript as follows:
The primary outcome in our study was actual retrieved oocyte number. We contend that to obtain more embryos, using retrieved oocyte number as a reference would be superior to using circulating surrogate markers of ovarian reserve. The number of retrieved oocytes was also positively correlated with pregnancy outcome. The number of retrieved oocytes in relation to the total dose of ovarian stimulation drugs could reflect the ovarian response. However, a retrospective study [24] reported a negative effect of salpingectomy history on AMH levels but not on the retrieved oocyte number for women with infertility, which differs from our study results. Nevertheless, distinct from our study, short and minimal stimulation protocols were applied for controlled ovarian hyperstimulation in that retrospective study. In the present study, we solely used the GnRH antagonist protocol for controlled ovarian stimulation and adjusted the dosage to obtain the optimal response. Variations in stimulation protocol, total gonadotropin dosage, stimulation interval, baseline ovarian reserve, and (potentially) blood flow in the ovaries may have influenced the numbers of retrieved oocytes.
Comment 3. In Table 2, the history of salpingectomy is not statistically significant in full model multivariate analysis. The author should explain this point.
Response 3:
The univariate analysis indicated that factors such as salpingectomy history, AMH, and AFC were all significantly associated with the number of retrieved oocytes. However, because the AMH and AFC had more direct and stronger correlations with the retrieved oocyte number than did history of salpingectomy, the effect of salpingectomy history was no longer significant after applying the full model of multivariate analysis that included adjustment for AMH level and AFC. This has been described on page 13 of the revised manuscript, lines 235–241.
Comment 4. The author should explain the limitation of this study. The result was not conclusive. There are some limitations regarding retrospective design, sample size, or baseline difference between two groups. As mentioned in the Discussion, it is also possible that the baseline difference of AFC and AMH was not the result of salpingectomy but other pelvic conditions.
Response 4:
This study has several limitations, including the retrospective study design, small sample size, and lack of measurement before salpingectomy. In addition, because we only selected women without underlying tubal disease as controls, those women with tubal disease but without tubal surgery history were not considered in this study. We have addressed these limitations in our revised manuscript in the “Discussion” section, pages 19 and 20, lines 388–394.
Comment 5. In figure 2 and 3, p-values of Kruskal–Wallis tests are needed. The correction method should be shown to compare groups (e.g., Bonferroni correction).
Response 5:
In accordance with your suggestion, we have analyzed the data by applying a nonparametric Kruskal–Wallis test for the data in Figs 2 and 3. However, because the Bonferroni test is reportedly too stringent to identify the between-group differences with such a small sample size, we used the Hochberg correction method for post hoc testing instead. We have described these procedures in the revised “Statistical Analysis” section and illustrated the results in the revised Figs 2 and 3.
Comment 6. Significant figures of p-values are not the same. (Figure 1A p=0.006, Figure 2 and 3 p<0.05, and p<0.01 are used in tables).
Response 6:
We have amended all P-value notation in our revised manuscript in accordance with the conventional mode of representation. If P values are between .9 and .001, the actual number is presented. P values of >.9 or <.001 are presented as “>.9” or “<.001.”
Comment 7. The author should decrease tone, especially in conclusion, because this study has several limitations.
Response 7:
We have rewritten the conclusion (in the last paragraph of the “Discussion” section) in our revised manuscript. Rather than the original stronger recommendation, we have changed the sentence to suggest directing greater attention toward ovarian response in women who underwent IVF with infertility, without sufficient ovarian reserves, and with salpingectomy history.
# Reviewer 2’ s comments: Dear Authors,
The subject of the study is current. A clear, simple and understandable writing language was used in the article. I believe it will benefit the reader. This is a good study comparing the number of oocytes collected after salpingectomy. Congratulations to the authors.
Below are my recommendations for the study.
Best regards
Comment 1. Some English grammar mistakes should be corrected.
Response 1:
Thank you for your valuable comments and suggestions. We apologize for the sporadic grammar mistakes in our manuscript. We have revised our manuscript with the help of an English-language editing service and have attached the relevant certificate as a supplementary file.
Comment 2. I suggest that some studies comparing the histopathological effects of salpingectomy and proximal tubal occlusion procedures on ovarian tissue should be given as examples [e.g. Atilgan R, Pala Ş, Kuloğlu T, Şanli C, Yavuzkir Ş, Özkan ZS. Comparison of the efficacy between bilateral proximal tubal occlusion and total salpingectomy on ovarian reserve and the cholinergic system: an experimental study. Turk J Med Sci. 2020 Jun 23;50(4):1097-1105. doi: 10.3906/sag-2002-179. ..................
Atilgan R, Kuloğlu T, Boztosun A, Orak U, Baspinar M, Can B, Sapmaz E. Investigation of the effects of unilateral total salpingectomy on ovarian proliferating cell nuclear antigen and follicular reserve: experimental study. Eur J Obstet Gynecol Reprod Biol. 2015 May;188:56-60. doi: 10.1016/j.ejogrb.2015.02.028.]
Response 2:
We have cited these references as [18] and [19] and used the studies as examples in the “Introduction” section on page 6, lines 112–116 in our revised manuscript as follows:
An experimental study revealed that total salpingectomy in rats leads to more significant damage than proximal tubal occlusion in ovarian histopathology and the cholinergic system [18]. Another study also indicated that the unilateral total salpingectomy procedure can be detrimental to ipsilateral ovarian tissue as a result of ischemia–reperfusion injury [19].
Submitted filename:
PONE-D-21-34495R1Prior salpingectomy impairs the retrieved oocyte number in in vitro fertilization cycles of women under 35 years old without optimal ovarian reservePLOS ONE
Dear Dr. Chen,
Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.
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ACADEMIC EDITOR:
Although the paper has been improved, there are still some problems that need to be addressed:
The Authors stated in their response ‘the effect of salpingectomy history was no longer significant after applying the full model of multivariate analysis that included adjustment for AMH level and AFC’ This is a strong message that should be clear in the Abstract. The abstract needs to be improved as the message provided is misleading. Figure legends are missing. How are data presented in the bars? The choice of limits of AMH (4 ng/mL) and AFC (12) for the subgroup analysis needs to be justified.
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Additional Editor Comments:
Although the paper has been improved, there are still some problems that need to be addressed:
1. The Authors stated in their response ‘the effect of salpingectomy history was no longer significant after applying the full model of multivariate analysis that included adjustment for AMH level and AFC’ This is a strong message that should be clear in the Abstract.
2. The abstract needs to be improved as the message provided is misleading.
3. Figure legends are missing. How are data presented in the bars?
4. The choice of limits of AMH (4 ng/mL) and AFC (12) for the subgroup analysis needs to be justified.
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Reviewer #1: All comments have been addressed
Reviewer #2: All comments have been addressed
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Dear Academic editor:
We greatly appreciated the valuable comments for improving our study. We have revised our manuscript accordingly and for adherence to the journal requirements. Our point-by-point responses to your comments are as follows.
# Academic Editor Comments
Although the paper has been improved, there are still some problems that need to be addressed:
Comment 1. The Authors stated in their response ‘the effect of salpingectomy history was no longer significant after applying the full model of multivariate analysis that included adjustment for AMH level and AFC’ This is a strong message that should be clear in the Abstract.
Response 1: Indeed, this message should be clear, and we have added in the Abstract, subtitled “measurements and main results”, line 64-69. Also, we have modified the context of the “conclusion” section in the Abstract with highlighting the message as stated above.
The problem that univariate regression analysis in our study indicated that factors such as salpingectomy history, AMH, and AFC were all significantly associated with the number of retrieved oocytes. However, in the multivariate-adjusted complete model, only AFC and AMH levels continued to exhibit significant associations with the number of retrieved oocytes. The explanation is that the effect of previous salpingectomy toward ovarian response are not as direct as ovarian surrogate biomarkers, which had been collected just around the time of controlled ovarian stimulation and transvaginal oocytes retrieval.
Salpingectomy impaired the circulation of ovary and may cause ischemic-reperfusion injury, and indirectly affect the ovarian function and response to fertility drugs afterwards. Therefore, in the full model of multivariate analysis, we can see that AFC and AMH have more direct influences toward number of retrieved oocytes than other factors.
Comment 2. The abstract needs to be improved as the message provided is misleading.
Response 2: Thank you for the comments and suggestions. We have added the important message of our statistical results in the Abstract, subtitled” measurements and main results” and “conclusion”. Although the full mode of multivariate analysis did not reveal the negative impact of previous salpingectomy on the number of retrieved oocytes, the detrimental effect to the ovarian function and response still presented via the decreased ovarian surrogate markers (AFC and AMH). Therefore, infertile patients with previous salpingectomies and suboptimal ovarian reserve should be paid attention to their ovarian response, however, postsurgical AMH and AFC levels still possess a more direct predictive value on ovarian response than the history of salpingectomy.
Comment 3. Figure legends are missing. How are data presented in the bars?
Response 3: We do apologize for the mistakes of incomplete figure legends. According to the policy of PLOS ONE journal for figure legends, we inserted the figure legends (including Fig. 1 to 3) by the way of inlay in the Manuscript, page 14 and 16. The data in the bars, including the values of means, standard deviations, were provided in the minimal data set of supplementary files. P values presented as an actual number in the figure above the bar plot when there was a significant difference.
Comment 4. The choice of limits of AMH (4 ng/mL) and AFC (12) for the subgroup analysis needs to be justified.
Response 4: In the full mode of multivariate analysis within our study, we found that AMH and AFC continued to be significantly associated with the number of retrieved oocytes. We further divided the subgroups with different level of surrogate ovarian biomarkers to realize the impact on ovarian response.
The cutoff value for AMH (4 ng/mL) was based on the reported 75th percentile of AMH levels of generally healthy Chinese women aged 35 years by the reference [21], BJOG 2020;127(6):720-8. The 75th percentile of AMH levels between 35 to 36 year-old chinese women lies between 4.229 to 3.973 ng/mL, which can be found in the Table 1 of the reference. Another reason for the cutoff value is because the limited case number in our study, we chose accordingly rather than calculated median AMH of our study. The cutoff value for AFC (12 follicles) was based on the calculated median AFC of all enrolled patients in our study. Above description was written in the Materials and Methods, section “Controlled ovarian stimulation and outcome measures” last two sentences.
The reason we used subgroup analysis to distinguish the patients with optimal ovarian reserve, which can be normal or hyper-responders and often with plenty number of retrieved oocytes and could mask the effect of history of salpingectomy.
Submitted filename:
Prior salpingectomy impairs the retrieved oocyte number in in vitro fertilization cycles of women under 35 years old without optimal ovarian reserve
PONE-D-21-34495R2
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PONE-D-21-34495R2
Prior salpingectomy impairs the retrieved oocyte number in
Dear Dr. Chen:
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