Title: Safety and efficacy of ninjin’yoeito along with iron supplementation therapy for
preoperative anemia, fatigue, and anxiety in patients with gynecological disease: an open-label,
single-center, randomized phase-II trial
Version: 2 Date: 25 Mar 2022
Reviewer's report:
Dear Editors and authors,
Thank you for the opportunity to review this randomized controlled trial titled
“Efficacy of ninjin’yoeito for preoperative anemia, fatigue, and anxiety in patients with
gynecological disease: an open-label, single-center, randomized phase-II trial “ At this point
in time, this study has several limitations and a considerable amount of work needs to be
done to improve its quality. In my opinion, ALL STUDIES should be prospective registered.
According to World Health Organization, I discourage retrospective registration. Investigators
should register trials that began enrolling patients if they wish to submit them to a journal that
follows the ICMJE policy. However, actually The ICMJE journals will accept “retrospective
registration”. Due to retrospectively registered (in my opinion  the main limitation of this
study) the length of time between the start date of the study (patient enrolment) and the date of
registration should be included in this study.
My main areas of concerns are described below:
Pag. 5 Lines 52-53. Authors must be backed up with numerical data
Pag 5. Lines 53-54.  This sentence need support, please include reference. “Most patients with
gynecological diseases have iron deficiency anemia because of hypermenorrhea or abnormal
menstruation”
Pag. 5 Line 55. How preoperative anemia can affect surgical outcomes? Describe outcomes can
be affected.
Pag 5. Line 56.  Describe postoperative complications. Give example and explication
Pag 5. Line 56.  Revise reference, it is not correct style
Pag. 5. Line 60-61.  Add cite, this percentage is very big. Justification is necessary.
Pag 5. Line 62. Is the same lack of sleep that reduce sleep quality? In this study authors register
sleep quality.
Pag 5. Line 62. Any type of cancer? “history of cancer”
Pag 6. Line 75. Please included more information how and which herbs is more adequate to
anemia, fatigue and anxiety.
Pag 7. Line 87. Please improve the aim of the study definition and include the authors' hypothesis
Pag 7. Line 98. Include a reference to the Declaration of Helsinki.  Please include CONSORT
recommendations.
Pag 8. Line 105. Why only women aged 20 or older? Women aged 18 why not?
Pag 8. Line 118. Were participants blinded to intervention?
Pag 8. Line 133. Why have you selected CFS  to assess fatigue? Fatigue severity scale permit to
assess fatigue without any bias. According to description to gynecologic diseases, these diseases
involving the female reproductive tract such as benign and malignant tumors, pregnancy-related
diseases, infection, and endocrine diseases. Was a selection criterion only women with a tumor?
This information is not described. Then you need revise the tittle.
Include information about psychometric properties for all questionnaires. were the ceiling and
floor effects explored in each instrument?
Pag 10. Line 154. Not start a sentence with a number. English grammar.
Please included more information about gynecological disease, Table 1. How many time patients
suffer tumors? Why do you want to say with menstruation? Menstruation refer to pregnancy-
related diseases? Marital status? Level of education? Employment status? Type of cancer/tumor?
Figo stage?
Give more information about hormonal therapy? Time? Doses? Frequency?
Please include all components for PSQI.
How you registered anxiety? In my opinion a specific instrument to assess anxiety is necessary.
It no possible register anxiety with CFS.
Please included a specific description of intervention. It is impossible to consult STORK for not
Japan speakers. I have lots and lots of doubts about intervention.
This study requires a sample size calculation. This is other important limitation.
A comparison between group after intervention is necessary. The results are very strangers. It is
really stranger not difference between pre-post intervention for PSQI  in Iron supplementation
group
In my opinion, this study has several limitations. Authors should analyze data using Kruskal-
Wallis. Then, they may explore differences post intervention between groups.  Use post hoc
analysis, Tukey’s range test.
According to analysis revision, discussion will be modified.
Please included as limitation retrospective register, not sample size calculation.
Pag. 16. Line 253. You do not if NYT improve QOL. Please, delete this sentence.