Inflammation and Preterm Birth: A Systematic Review

Round 1

Reviewer 1 Report

The reviewer don't feel like the manuscript was substantially improve for the previous version.

Author Response

The authors are sorry for the reviewer’s opinion. All the amendments and suggestions made by the reviewer were performed; as so, we do not really understand this sentence.

Reviewer 2 Report

The Authors analyzed the inflammatory mechanisms that have a critical in parturition and collectively initiate labour. They include articles concerning birth and inflammation, and searches on the electronic databases MEDLINE, Embase, Scopus, Web of Science and Cochrane Library, from 2017 until 2021. They show that the difference between term and preterm labour (PTB) could involve a pre-existing disproportion of decidual inflammatory signalling, or an unusual stimulus prompting inflammatory pathways and the inflammatory reduction could arrest PTB.

This review is clear and simple to read and I suggest only minor changes.

1) to correct in all manuscript several words in which fetal or fetus without “o” was written.

2) In figure 1, the caption is missing

3) it is possible to insert evidences on N-acylethanolamines (NAEs), as N-arachidonoylethanolamine (AEA), N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA) that could change in women at high risk for preterm birth (PTB) and from a single blood test is possible to have plasma NAEs could offer great ability as a predictors of PTB.

4) in page 8 there is a sentence: “Therefore, we can assume that parturition is inflammation-induced, whereby proinflammatory/prolabour stimuli induce nPRA mediated adjustments [14], and that the key mechanism by which P4 is believed to block labour is by decreasing uterine cell’ responsiveness to prolabour/proinflammatory stimuli [14].” The second “prolabour/proinflammatory” maybe is “proinflammatory/prolabour” as the first.

Author Response

1) to correct in all manuscript several words in which fetal or fetus without “o” was written.

All the amendments were made

2) In figure 1, the caption is missing

Figure 1 Caption was added

3) it is possible to insert evidences on N-acylethanolamines (NAEs), as N-arachidonoylethanolamine (AEA), N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA) that could change in women at high risk for preterm birth (PTB) and from a single blood test is possible to have plasma NAEs could offer great ability as a predictors of PTB.

Thanks for the suggestion. The following sentence was added in 4.4. New approaches in PTB treatment, VIII. Polyunsaturated fatty acids (PUFA) and lipid metabolites: page 10: “Moreover, plasma N-acylethanolamines were recently proposed as a single simple test that could be used to predict PTB in high-risk women [20]”.

4) in page 8 there is a sentence: “Therefore, we can assume that parturition is inflammation-induced, whereby proinflammatory/prolabour stimuli induce nPRA mediated adjustments [14], and that the key mechanism by which P4 is believed to block labour is by decreasing uterine cell’ responsiveness to prolabour/proinflammatory stimuli [14].” The second “prolabour/proinflammatory” maybe is “proinflammatory/prolabour” as the first.

Thank you for the remark: the proper adjustment was made.

Reviewer 3 Report

Many thanks for this opportunity. I read with interest the paper.

I find it a good paper that need only minor revision

1. IN introduction section please add the global burden of pretherm baby and the wordwilde distribution
2. Prima is ok and also prospero registration
3. Figure is very clear and help to understand the great paper of authors
4. Add more consideration in genetic factors 
5. In new approach please clarify the best practice in low income country than in high income

Congratualtions for your paper

Author Response

1. In introduction section please add the global burden of pretherm baby and the worldwide distribution

 

The following sentence was included in the Introduction, page 2: “Preterm birth (PTB) affects 11% of all births, corresponding to 15 million babies/annually, of which 2/3 are spontaneous. The rates of PTB  range from  5% in Europe, 10.2% in USA, to 18% in certain African countries”

 

2. Prisma is ok and also Prospero registration

 

3. Figure is very clear and help to understand the great paper of authors

 

4. Add more consideration in genetic factors 

 

The following sentence was included in Genetic factors and PTB, page 7: “Genetic factors play a role in PTB as it shows a familial aggregation; has measures of heritability; can be detected by susceptibility genes; and reveals a racial disparity. Also, it recurs in mothers and women who were preterm babies are at higher risk of delivering preterm themselves.”

 

5. In new approach please clarify the best practice in low income country than in high income

 

The best practice is often limited by the price. As for prices, Rytvela is the most expensive and naloxone the least.

As so, the following sentence was included in page 10, just before the “Final comment”: “According to these results, the best candidates for future PTB treatments are CSAIDs (Naloxone could be chosen for low-income countries) and IL-1 receptor inhibitor (Rytvela might be the ideal for high-income countries).

Congratulations for your paper

Thank you!

Reviewer 4 Report

In my opinion, the manuscript submitted for evaluation can be published without further corrections. It meets the requirements of a review work, the literature is modern, it covers research from the last 5 years. The topic is topical, it is part of the work on the pathogenesis of preterm labor.

Author Response

Thank you!

Round 2

Reviewer 1 Report

This systematic review aims to investigate the recent knowledge on PTB and inflammation. Overall, the reviewer finds the manuscript hard to follow, with limited emphasis on the inflammatory response in PTB. The background information about PTB is scattered between the introduction and the discussion. Although the authors mention they only selected articles including PTB, most of the discussion is about inflammation during normal delivery and even in the section about PTB, most of the information is regarding parturition processes. Even when the authors discuss inflammation in PTB few details were given (e.g. IL-10). Moreover, the section on new therapies introduces many new inflammatory pathways that were not introduced in the previous section. Overall, the reviewer find this review falling short of what the title/introduction suggest.

Moreover, the search strategy worries me, the period is short, and the keywords are not in accordance with the objectives of the study (why do they include "genetic predisposition" and not "chemokines", why "prostaglandins" when it is not described in the objectives of the work?)

Reviewer 2 Report

I thank the Authors to the modifications and the review could be accepted in present form.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

In general, I think that this is an article that goes into little depth, and lacks organization.

• In the introduction, the paragraph on animal models, would be out of the objective of the review.
• It is not very clear to me what this work contributes to what is already in the literature in systematic reviews such as PMID: 31581042 or PMID: 20664401.
• There are concepts that I do not understand exactly what they mean ("placental health", "damaged membranes", "PTB syndrome"...).
• the search strategy worries me, the period is short, and the keywords are not in accordance with the objectives of the study (why do they include "genetic predisposition" and not "chemokines", why "prostaglandins" when it is not described in the objectives of the work?)
• section 4.1. does not mention anything about prematurity, it is out of focus with the review. Perhaps the most interesting part starts in section 4.3. But, again, section 4.4. is outside the objectives of the paper, because they explore treatments for the control of prematurity? weren't they studying the influence of inflammation on preterm delivery?

In other things,

• the abstract has form errors, please consult the author's guidelines.
• Normally could already be considered physiological.
• The English should be revised, there are many contractions, literary and non-formal expressions that are not appropriate for a scientific article.
• Add the flow diagram to the main text, in material and methods.
• The first paragraph of results is repeated in the material and methods.

Reviewer 2 Report

This systematic review aims to investigate the recent knowledge on PTB and inflammation. Overall, the reviewer finds the manuscript hard to follow, with limited emphasis on the inflammatory response in PTB. The background information about PTB is scattered between the introduction and the discussion. Although the authors mention they only selected articles including PTB, most of the discussion is about inflammation during normal delivery and even in the section about PTB, most of the information is regarding parturition processes. Even when the authors discuss inflammation in PTB few details were given (e.g. IL-10). Moreover, the section on new therapies introduces many new inflammatory pathways that were not introduced in the previous section. Overall, the reviewer find this review falling short of what the title/introduction suggest.

Minor comments:

- Introduction (before last para): the author should more carefull with their statement, as Barley et al states : "However, in pathological pregnancies, rodent models reproduce many of the innate immunological features seen in complicated human pregnancy and consequently, may prove to be useful."

- Figure resolution needs to be increased.

- Interferon should be abbreviated to IFN (not INF).