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  • Ramilya K. Potapova1,*,
  • Madina E. Ospanova1 and
  • Saniya A. Abdrakhmanova1
  • et al.

Reviewer 1: Mats Brannstrom Reviewer 2: Anonymous Reviewer 3: Anonymous Reviewer 4: Anonymous

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This article deals with an interesting topic within Reproductive medicine.

The article is a case series with the endpoint clinical pregnancy. The sample size is small with heterogeneity within the group. there is no control group for comparison.

The Q whether PRP is beneficial for IVf outcome can only be determined in a proper RCT with the primary outcome of live birth rate per ET or per OPU.

The present article will not have any value to the field and may merely confuse/mislead clnicians and patients.

Author Response

1 Reviewer’s comment: This article addresses an interesting topic in reproductive medicine. The manuscript presents a case series in which the final outcome was clinical pregnancy. The sample size is small, and there is no intragroup heterogeneity. No control group is available for comparison.

Authors’ response: As a control group, we used the pre-inclusion data of the same women who later comprised the experimental group. We considered this comparison acceptable, as all women in the experimental group had undergone multiple IVF attempts prior to the study, all of which had been unsuccessful.

2 Reviewer’s comment:

Whether PRP is beneficial for IVF outcomes can only be determined through a proper randomized controlled trial with the primary outcome being live birth rate per embryo or per ovulation. This manuscript does not provide value for the field and may only confuse or mislead clinicians and patients.

Authors’ response: A single-center prospective interventional clinical study was conducted (all participants received PRP, and the comparison was made with baseline data before treatment–before/after design).

All changes made to the manuscript in accordance with the reviewers' comments are highlighted in color.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Dear authors,

The effect of platelet-rich plasma on reproductive outcomes in women with repeated embryo transfer failures

INTRODUCCTION The introduction is clear and well organized. The main topic of the study is properly introduced with detailed aims.

METHODS AND MATERIALS The anticoagulant employed for blood plasma collection, or the kit employed for PRP extraction must be specified in the section of "preparation of autologous PRP".

RESULTS I suggest changing the graph in Figure 8 to improve clarity and better demonstrate the significance, given that endometrial thickness is one of the study's primary outcomes.

Author Response

1 Reviewer’s comment: The anticoagulant used for blood plasma collection, or the kit used for PRP extraction, should be specified in the “Preparation of Autologous PRP” section.

Authors’ response: A double blood bag (hemacon) was used–this is a sterile disposable system consisting of two interconnected plastic bags intended for whole blood collection and processing. It includes two bags: the primary bag contains the anticoagulant CPDA-1 (Citrate–Phosphate–Dextrose–Adenine), and the secondary empty bag is used for separating and transferring plasma and/or red blood cells after centrifugation. Information about the anticoagulant used has been added to the “Preparation of Autologous PRP” section.

2 Reviewer’s comment: I suggest modifying the graph in Figure 8 for better clarity and improved visualization of significance, considering that endometrial thickness is one of the main outcomes of the study.

Authors’ response: The graph in Figure 8 has been modified.

All changes made to the manuscript in accordance with the reviewers' comments are highlighted in color.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Introduction is too long and discussion is short . please rearrange . include more studies to compare with your results

Results that are encessary for objectives only can be represented

Author Response

1 Reviewer’s comment: The introduction is too long, and the discussion section is too short. Please rearrange them. Include more studies to compare with your results.

Authors’ response: New studies have been added to the Discussion section, and this section has been expanded.

2 Reviewer’s comment: Only results necessary to achieve the objectives should be presented.

Authors’ response: All results obtained during the study are presented in the article. Some evaluated parameters did not show statistical significance, but they were still included, as this information may be useful to other researchers.

All changes made to the manuscript in accordance with the reviewers' comments are highlighted in color.

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

Dear Authors

Thanks for your valuable study

1- Please mention the type of study in the manuscript title, abstract, and method section.

2-Please describe why you didn't compare the PRP efficacy with the control group?

3-Since the age range (27 to 52 years) you included in the study is wide, and endometrial function and response to PRP vary across this wide range, how did you manage this bias?

4-Please clarify the inclusion and exclusion criteria.

5-How did you calculate the sample size?

6- Age range in lines 146 and 157 is different. Please edit it.

7-Please clarify how you confirmed chronic endometritis.

8-Since you collected 350-450 cc whole blood from participants, did you exclude anemic women from the study?

9-Please explain why you freeze and thaw the PRP suspension?

10-Please describe the size of the catheter used for PRP infusion

11-Which part of the menstrual cycle did you infuse PRP?

12-What was the interval of the PRP infusions?

Author Response

Thank you for your comments, they have all been taken into account.

1 Reviewer’s comment: Please indicate the type of study in the manuscript title, abstract, and Methods section.

Authors’ response: We have added information about the study type to the specified sections. This is a single-center prospective interventional clinical study (all participants receive PRP, and the comparison is made with baseline data before treatment–before/after design).

 

2 Reviewer’s comment: Please describe why you did not compare PRP effectiveness with a control group.

Authors’ response: As a control group, we used the pre-inclusion data of the same women who later formed the experimental group. We considered this comparison acceptable, as all women in the experimental group had undergone multiple IVF attempts prior to the study, all of which were unsuccessful.

 

3 Reviewer’s comment: Since the age range you included in the study (27 to 52 years) is wide, and endometrial function and response to PRP vary across this range, how did you address this bias?

Authors’ response: According to our research team, in this case age does not have a significant impact on endometrial thickness or structure, which are individual for each patient and therefore do not influence the outcome of PRP therapy. The key factors determining embryo transfer success are normal levels of sex hormones and the presence of a menstrual cycle; in addition, all patients undergoing IVF receive hormone replacement therapy, which effectively equalizes their chances.

 

4 Reviewer’s comment: Please specify the inclusion and exclusion criteria.

Authors’ response:

Inclusion criteria:

  1. signed informed consent to participate in the study;
  2. age 18 to 52 years;
  3. infertility lasting more than 12 months;
  4. confirmed chronic endometritis;
  5. recurrent implantation failure (this newly added criterion has been included in the Methods section).

Exclusion criteria:

  1. medical contraindications to pregnancy;
  2. patient’s refusal to continue participation in the study or withdrawal of previously signed informed consent.

 

5 Reviewer’s comment: How did you calculate the sample size?

Authors’ response: In a “before–after” study design (paired measurements), sample size calculation is performed to assess changes in the same patients before and after the intervention (e.g., PRP administration in women with infertility). Paired observations are compared using a paired t-test. The sample size is calculated based on the desired statistical power (80–90%) and the significance level (typically α = 0.05).

Formula

n = ((Z_(1-α/2) + Z_(1-β)) * σ_d / δ)^2

where:

n – number of paired observations,

Z_(1-α/2) – quantile of the normal distribution (1.96 for α=0.05),

Z_(1-β) – quantile for statistical power (0.84 for 80% power),

δ – expected mean difference (effect),

σ_d – standard deviation of the differences.

 

δ = 2,0; σ_d = 4,0; α=0,05; power  80%

Z_(1-α/2) + Z_(1-β) = 2,8

n = (2,8 * 4 / 2)^2 = 31,36 ≈ 32 participants

Considering a 15% dropout rate: 32 / (1 – 0.15) ≈ 38.

Final: Approximately 30–40 participants provide adequate power for a moderate effect size.

 

6 Reviewer’s comment: The age range in lines 146 and 157 differs. Please revise it.

Authors’ response: The age range in line 146 refers to the ages of the patients who were actually included in the study, while the age range in line 157 under the inclusion criteria refers to the acceptable age for participation in the study. Thus, we considered women aged 18 to 52 years for inclusion, but among the enrolled participants the minimum age was 27 years.

 

7 Reviewer’s comment: Please clarify how you confirmed chronic endometritis.

Authors’ response: The patients underwent hysteroscopy for visual assessment of the endometrium and a histological examination of endometrial tissue. Based on these results, the diagnosis was established.

 

8 Reviewer’s comment: Since you collected 350–450 cm³ of whole blood from participants, did you exclude women with anemia from the study?

Authors’ response: After enrollment and before PRP therapy, all participants underwent a hemoglobin test. All participants had normal hemoglobin levels, which is presented in the Results section of the study.

 

9 Reviewer’s comment: Please explain why you freeze and thaw the PRP suspension.

Authors’ response: For the preparation of PORFT, platelet concentrate undergoes a single freezing at −20 °C or below to induce cryodestruction of platelets and release growth factors into the plasma. After obtaining bacteriological test results confirming sterility, the product is thawed for subsequent centrifugation to remove debris from the lysed platelets and to achieve a more homogeneous consistency of the final product, which is then dispensed into sterile glass vials. The vials with the prepared PORFT are frozen again for long-term storage. The shelf life of PORFT is 1 year.

 

10 Reviewer’s comment: Please describe the size of the catheter used for PRP infusion.

Authors’ response: An intrauterine insemination catheter, Intermediate type, 180 mm, was used.

 

11 Reviewer’s comment: In which phase of the menstrual cycle did you administer PRP?

Authors’ response: PRP was administered during the first phase of the menstrual cycle – the proliferative phase.

 

12 Reviewer’s comment: What was the interval between PRP administrations?

Authors’ response: PRP infusions were performed without intervals, administered consecutively throughout the proliferative phase for several days in a row (daily for 3 to 7 days).

 

All changes made to the manuscript in accordance with the reviewers' comments are highlighted in color.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I still think that the design is not appropriate to answer the question whether PPR is beneficial. 

Author Response

Reviewer’s comment: I still think that the design is not appropriate to answer the question whether PPR is beneficial.

Authors’ response: Thank you for your comment, however, unfortunately, it is not possible to change the design at the moment since the results have already been received.

Reviewer 4 Report

Comments and Suggestions for Authors

Dear Authors

Thanks for your responses.

1-For point 3, please add a reference according to the literature.

2-Please add an explanation of comment number 6 in the manuscript text.

 

Author Response

Dear Reviewer,

Thanks for your comments.

Reviewer’s comment:

1 - For point 3, please add a reference according to the literature.

Authors’ response: Studies confirming the lack of a correlation between age and endometrial thickness:

  1. Tsuda H, Ito YM, Todo Y, et al. Measurement of endometrial thickness in premenopausal women in office gynecology. Reprod Med Biol. 2017;17(1):29-35. Published 2017 Sep 16. doi:10.1002/rmb2.12062 https://pmc.ncbi.nlm.nih.gov/articles/PMC5768977/

Conclusion: In this prospective study of 849 premenopausal women (mean age 38.5 years) undergoing cervical cancer screening, the median endometrial thickness was 8.6 mm. Analysis showed that endometrial thickness (ET) was not associated with age, symptoms, obstetric history, or geographic location. ET varied strictly according to the phase of the menstrual cycle (from 5.4 mm immediately after menstruation to 11.1 mm on day 18).

  1. Hsu, M. et al. Endometrial thickness in anovulatory women of reproductive age. Fertility and Sterility, Volume 96, Issue 3, S131. https://www.researchgate.net/publication/251724130_Endometrial_thickness_in_anovulatory_women_of_reproductive_age

Conclusion: A study of 62 women of reproductive age (22–39 years) with prolonged anovulation showed that endometrial thickness did not correlate with age.

 

2 - Please add an explanation of comment number 6 in the manuscript text.

Authors’ response: We have added clarifying information about the age range to both lines.

All changes made to the manuscript are highlighted in color.